Prolongación del tiempo QT
Eventos adversos de medicamentos
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de mexiletina, diazepam y omeprazol. Consulte también la información especializada pertinente.
|Mexiletina||0.97 [0.61,3.48] 1,2||n.a.||0.97|
|Diazepam||1.3 [1.02,1.54] 3||1||1.3|
|Omeprazol||1 [0.66,7.23] 3||1||1|
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. La exposición a diazepam aumenta al 110 %, cuando se combina con mexiletina (100%) y omeprazol (130%). El AUC se encuentra entre 0 % y 100 % dependiendo del
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La mexiletina tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es de 6.3 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 25.2 horas. La unión a proteínas [ Pb ] es relativamente débil al 100 % y el volumen de distribución [ Vd ] es muy grande a 446 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede conducir a una mayor exposición. El metabolismo tiene lugar a través de CYP1A2, CYP2B6 y CYP2D6, entre otros.
La diazepam tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es relativamente extensa a las 36 horas y los niveles plasmáticos constantes [ Css ] sólo se alcanzan después de más de 144 horas. La unión a proteínas [ Pb ] es 100 % fuerte y el volumen de distribución [ Vd ] es muy grande a 83 litros. Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede conducir a una mayor exposición. El metabolismo tiene lugar a través de CYP2B6, CYP2C19 y CYP3A4, entre otros.
La omeprazol tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es relativamente corta a las 0.9 horas y los niveles plasmáticos constantes [ Css ] se alcanzan rápidamente. La unión a proteínas [ Pb ] es moderadamente fuerte al 100 % y el volumen de distribución [ Vd ] es pequeño a 21 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede conducir a una mayor exposición. El metabolismo tiene lugar a través de CYP2C19 y CYP3A4, entre otros y el transporte activo tiene lugar especialmente a través de PGP.
|Efectos serotoninérgicos a||0||Ø||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la mexiletina, diazepam ni la omeprazol aumentan la actividad serotoninérgica.
|Kiesel & Durán b||1||Ø||+||Ø|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La diazepam solo tiene un efecto leve sobre el sistema anticolinérgico. El riesgo de síndrome anticolinérgico con este medicamento es relativamente bajo si la dosis se encuentra en el rango habitual. Según nuestro conocimiento, ni la mexiletina ni la omeprazol aumentan la actividad anticolinérgica.
Prolongación del tiempo QT
Recomendación: Asegúrese de minimizar los factores de riesgo que puedan influir. Deben compensarse los desequilibrios electrolíticos, como los niveles bajos de calcio, potasio y magnesio. Debe utilizarse la dosis mínima eficaz de omeprazol.
Clasificación: La omeprazol puede prolongar potencialmente el tiempo QT y, si existen factores de riesgo, pueden producirse arritmias del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT de la mexiletina y diazepam.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||mex||dia||ome|
|Sintiéndose nervioso||8.2 %||8.2||n.a.||n.a.|
|Dolor de cabeza||7.0 %||n.a.||n.a.||7.0|
|Dolor abdominal||5.0 %||n.a.||n.a.||5.0|
Reacciones alérgicas de la piel: omeprazol
Lupus eritematoso cutáneo: omeprazol
Eritema multiforme: omeprazol
Síndrome de Stevens-Johnson: omeprazol, mexiletina
Necrolisis epidérmica toxica: omeprazol
Problema de coordinación: mexiletina
Incautación: diazepam, mexiletina
Visión borrosa: mexiletina
Efecto hangover: diazepam
Efecto rebote: diazepam
Diarrea por clostridium difficile: omeprazol
Bloqueo auriculoventricular: mexiletina
Insuficiencia cardiaca: mexiletina
Depresion respiratoria: diazepam
Agranulocitosis: omeprazol, mexiletina
Leucopenia: omeprazol, mexiletina
Trombocitopenia: omeprazol, mexiletina
Transaminasas elevadas: omeprazol
Encefalopatía hepática: omeprazol
Insuficiencia hepática: omeprazol
Reacción anafiláctica: omeprazol
Reacción de hipersensibilidad: mexiletina
Lupus eritematoso: mexiletina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: No Abstract available
Abstract: The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg.kg-1 i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b.d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.
Abstract: Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.
Abstract: To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V1 and Vss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h-1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth - one third of the usual dose.
Abstract: The pharmacokinetics of omeprazole have been studied to varying extent in the mouse, rat, dog and in man. The drug is rapidly absorbed in all these species. The systemic availability is relatively high in the dog and in man provided the drug is protected from acidic degradation in the stomach. In man the fraction of the oral dose reaching the systemic circulation was found to increase from an average of 40.3 to 58.2% when the dose was raised from 10 to 40 mg, suggesting some dose-dependency in this parameter. The drug distributes rapidly to extra-vascular sites. The volume of distribution, V beta, in man is comparable to the volume of the extracellular water. The penetration into the red cells is low, the ratio between the concentration in whole blood and in plasma being about 0.6. Omeprazole is bound to about 95% to proteins in human plasma. The binding is lower in the dog and rat (90 and 87%, respectively). Omeprazole is eliminated almost completely by metabolism and no unchanged drug has been recovered in the urine in the species studied. Two metabolites, characterised as the sulfone and sulfide of omeprazole, have been identified and quantified in human plasma. The mean elimination half-life in man and in the dog is about 1 hour, whereas half-lives in the range of 5 to 15 minutes have been recorded in the mouse. In two studies in man, the mean total body clearance was 880 and 1097 ml X min-1, indicating that omeprazole belongs to the group of high clearance drugs. In the dog, too, the drug appears to be rapidly cleared from the blood, the mean total body clearance being about 10.5 ml X min-1 X kg-1. In the rat and dog, 20 to 30% of an i.v. or oral dose of omeprazole is excreted as metabolites in the urine and the remaining fraction is recovered in the faeces within three days after the administration. In man, the excretion of radioactivity via the kidneys is much more efficient and the recoveries in the excreta are approximately the reverse of those in the rat and dog. In vitro studies with rat liver microsome preparations suggest that omeprazole and cimetidine inhibit cytochrome P-450-mediated metabolic reactions to about the same extent in equimolar concentrations. However, since the molar daily dose of cimetidine will be 25 to 50 times higher than that of omeprazole, the latter might have less influence on the mixed function oxidase system than cimetidine.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Cimetidine, a commonly used H2-receptor antagonist, was found to interact adversely with many drugs, including class I antiarrhythmics such as lidocaine and quinidine. To test the effect of cimetidine on the kinetics of mexiletine, a class I antiarrhythmic similar to lidocaine, the absorption and disposition of mexiletine were followed in six healthy subjects before and after 1 week of cimetidine, 300 mg by mouth four times a day. Cimetidine did not alter the distribution and elimination of mexiletine, as shown by similar mean kinetics including total body clearance, AUC, and the elimination t1/2 before and after cimetidine treatment. Cimetidine did have a significant effect on mexiletine absorption, as demonstrated by a longer mean absorption t1/2 (from 0.20 +/- 0.14 to 0.61 +/- 0.35 hours), a longer mean time to peak mexiletine concentration (from 1.13 +/- 0.31 to 1.88 +/- 0.83 hours), and decreased mexiletine plasma concentration (from 0.74 +/- 0.19 to 0.59 +/- 0.15 mg/ml). We conclude that cimetidine does not alter the disposition of oral mexiletine in normal subjects.
Abstract: No Abstract available
Abstract: To study the effects of enzyme induction on its pharmacokinetics, a single oral dose of the new antiarrhythmic agent mexiletine hydrochloride 400 mg was administered to 8 healthy volunteers before and after treatment with rifampicin 300 mg b.i.d. for ten days. The absorption and distribution of mexiletine were not changed after rifampicin, but its elimination half-life fell from 8.5 +/- 0.8 h (mean +/- SE) to 5.0 +/- 0.4 h (p less than 0.01), and its nonrenal clearance increased from 435 +/- 68 ml/min to 711 +/- 101 ml/min (p less than 0.01). The mean renal clearance of mexiletine did not change, but it showed an exponential correlation with urinary pH. The amount of unchanged mexiletine excreted in urine over two days decreased from 32 +/- 7 to 18 +/- 3 mg (p less than 0.01). The half-life of antipyrine fell from 11.8 +/- 0.4 to 5.5 +/- 0.3 h and its clearance increased from 40 +/- 3 ml to 74 +/- 3 ml/min (p less than 0.01). There was a significant (p less than 0.05) positive linear correlation between both the half-lives and the clearances of antipyrine and mexiletine. The clearances were positively correlated with serum gamma-glutamyl transpeptidase. The results suggest that the dosage of mexiletine should be adjusted when enzyme inducing drugs are started or stopped during therapy with it.
Abstract: 1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15-90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml-1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10-20 mg of solution, and then usually after a delay of over 2 h.
Abstract: Single-dose kinetics of mexiletine (MEX) was studied in six healthy subjects after three different formulations. The respective doses were 200 mg (intravenous infusion), 400 mg (two conventional capsules), and 432 mg (sustained-release dosage forms). By a three-compartment open model with lag time the kinetic parameters of the drug were calculated from the experimental plasma level data. The mathematical analysis of the processes of distribution and elimination was restricted to the intravenous data only, and the resulting transfer constants were introduced into the evaluations of the oral experiments. With this procedure one common value for the plasma t 1/2 of elimination was obtained (t 1/2 gamma = 6.34 +/- 1.5 hr). Mean values for the total volume of distribution (Vdtot) and the total body clearance (Cltot) were 5.5 l/kg and 10.3 ml/min/kg. After capsules, peak plasma concentrations (Cmax = 0.77 microgram/ml) were reached after 2.2 hr. and the sustained-release form built up a flat maximum of concentration (Cmax = 0.34 microgram/ml) after 9.2 hr. Mexiletine is highly bioavailable, almost identical for the two oral formulations: 87.3% (capsule) and 78.7% (slow release). Under physiologic urinary pH1 7.5% to 9.2% of the dose was excreted unchanged by the kidneys.
Abstract: It was reported previously that mexiletine undergoes stereoselective disposition in humans and that formation of three of its major metabolites co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-mediated oxidation pathways of mexiletine are responsible for the stereoselective disposition of the racemate in humans. Fourteen healthy subjects (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) participated in this study. They received a single 200-mg oral dose of racemic mexiletine hydrochloride on two occasions: once alone and once during administration of low-dose quinidine (50 mg four times a day). Blood and urine samples were obtained over 48 hr after the administration of mexiletine and analyzed by a stereoselective high-performance liquid chromatography assay. As reported previously, RS-mexiletine disposition was altered by a genetically determined (PM) or drug-induced (quinidine) decrease in CYP2D6 activity. In contrast, R/S ratio of the apparent total and nonrenal clearances of mexiletine and the R/S ratio of the urinary recovery of both enantiomers were similar in EMs and PMs. Moreover, these ratios were unaltered by quinidine administration. Partial metabolic clearance of N-hydroxymexiletine glucuronide, a non-CYP2D6 dependent metabolite, was highly stereoselective; the R/S ratio was 11.3 +/- 3.4. This ratio was similar in subjects with either an EM or a PM phenotype and was not altered by quinidine administration. Thus, the results obtained in this study suggest that non-CYP2D6-dependent metabolic pathways are responsible for the stereoselective disposition of mexiletine in humans.
Abstract: Marked interindividual variation has been observed in the pharmacokinetics of the antiarrhythmic agent mexiletine. The fact that its urinary excretion is dependent on urinary pH may account, in part, for such variation. The influence that genetic differences in hepatic metabolism of the debrisoquine-type may have on mexiletine pharmacokinetics was considered in this study. The pharmacokinetics and urinary excretion of mexiletine (250 mg administered intravenously) were investigated in 5 rapid extensive metabolisers (EM), 5 slow EM and 5 poor metabolisers (PM) of debrisoquine, under conditions of controlled urinary pH. Mexiletine disposition kinetics was found to be altered in PM individuals. These subjects showed higher total area under the curve (AUC), (15.7 versus 8.16 micrograms.h.ml-1) prolonged elimination half-lives (in serum and urine) (serum: 18.5 versus 11.6 h, urine: 19.2 versus 11.7 h) and lower total clearance values compared with EM (216 versus 450 ml.min-1). In this respect, slow EM individuals generally presented intermediate values of those pharmacokinetic parameters. A higher incidence of adverse-effects was also observed among slow EM and PM subjects. It is concluded that genetic differences in mexiletine oxidation of the debrisoquine-type have an influence on its observed pharmacokinetic variability. The clinical consequences are discussed.
Abstract: The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study. Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml.h-1 kg-1; with ciprofloxacin: 12.3 ml.h-1 kg-1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l.kg-1; with ciprofloxacin: 1.1 l.kg-1). However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.
Abstract: 1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system. 2. Among the P450 forms tested, diazepam was significantly demethylated by CYP2B6, 2C9, 2C19, 3A4 and 3A5, with 2C19 exhibiting the highest rate at concentrations < 0.1 mM, and hydroxylated only by the latter three enzymes, with 3A5 being the most active. The N-demethylation activity of diazepam by 2C19 at a concentration of 20 microM was six times of that by 3A4. However, that by 2C9 was detected at only a trace level. 3. CYP2C19, 3A4 and 3A5 of the ten human P450s catalysed the 3-hydroxylation of nordiazepam, and 2B6, the 2C subfamily and the 3A subfamily catalysed the N-demethylation of temazepam. CYP3A4 exhibited the highest activity of nordiazepam 3-hydroxylation and temazepam N-demethylation. 4. Diazepam N-demethylation by human liver microsomes correlated with diazepam 3-hydroxylation, but not S-mephenytoin 4'-hydroxylation. 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.
Abstract: AIMS: Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism. METHODS: Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF). RESULTS: Mexiletine p- and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p- and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1'-hydroxylase activity (r = 0.907, P < 0.001 and r = 0.886, P < 0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p- and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYPIA2 to both mexiletine p- and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the Km values of the expressed CYP1A2 (approximately 15 microM) were almost identical with those of the expressed CYP2D6 (approximately 22 microM) and human liver microsomes. CONCLUSIONS: Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.
Abstract: Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed following oral administration with a bioavailability of about 90%. Peak plasma concentrations following oral administration occur within 1 to 4 hours and a linear relationship between dose and plasma concentration is observed in the dose range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 hours). It undergoes stereoselective disposition caused by extensive metabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabolites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine and m-hydroxy-mexiletine is genetically determined and cosegregates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity. On the other hand, CYP1A2 seems to be implicated in the N-oxidation of mexiletine. Various physiological, pathological, pharmacological and environmental factors influence the disposition of mexiletine. Myocardial infarction, opioid analgesics, atropine and antacids slow the rate of absorption, whereas metoclopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette smoking significantly enhance the rate of elimination of mexiletine, whereas ciprofloxacin, propafenone and liver cirrhosis decrease it. Cimetidine, ranitidine, fluconazole and omeprazole do not modify the disposition of mexiletine. Conversely, mexiletine is known to alter the disposition of other drugs, such as caffeine and theophylline. Factors affecting the elimination of mexiletine may be clinically important and dosage adjustments are often necessary.
Abstract: (R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-oxazepam (but not R-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-oxazepam glucuronidation. Furthermore, the apparent K(m) for UGT2B15 (29-35 microM) was similar to values determined for HLMs (43-60 microM). In contrast, R-oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent K(m) values for HLMs (256-303 microM) were most similar to UGT2B7 (333 microM) rather than UGT1A9 (12 microM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higher S-oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3alpha-diol. In conclusion, S-oxazepam is stereoselectively glucuronidated by UGT2B15, whereas R-oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-oxazepam glucuronidation in humans.
Abstract: The binding of drugs to plasma proteins is important to consider when concentrations in whole blood (eg, in forensic toxicology) are compared with therapeutic and toxic concentrations based on the analysis of plasma or serum. The plasma to whole blood distribution of diazepam (D) and its major metabolite nordiazepam (ND) was investigated under in vitro and ex vivo conditions. Studies in vitro were done by spiking whole blood with D and ND to give concentrations ranging from 0.1 to 1.0 microg/g. Venous blood was also obtained from hospital blood donors (n = 66) after informed consent. The hematocrit, hemoglobin, and water content of blood specimens were determined by routine procedures before D and ND were added to produce target concentrations of approximately 0.5 microg/g for each substance. The ex vivo work was done with blood specimens from hospital outpatients who were being medicated with D. Concentrations of D and ND were determined in body fluids by capillary column gas chromatography after adding prazepam as internal standard and solvent extraction with butyl acetate. The method limit of quantitation was 0.03 microg/g for both D and ND. The concentrations of D and ND were highest in plasma and lowest in erythrocytes. The plasma/blood (P/B) distribution ratios did not depend on drug concentration between 0.1 and 1.0 microg/g. The mean P/B ratios were 1.79:1 for D and 1.69:1 for ND when hematocrit was 45%. Furthermore, the P/B ratio for D (y) was positively correlated with blood hematocrit (x) and the regression equation was y = 0.636 + 0.025x (r = 0.86, P < 0.001). A similar strong association was found between the P/B ratio and hematocrit for ND (r = 0.79). P/B ratios of D and ND, blood hematocrit, hemoglobin, and the water content differed between sexes (P < 0.001). The overall mean P/B ratios for D and ND were 1.69 +/- 0.097 (+/- SD) and 1.62 +/- 0.08 (P < 0.001, n = 66) respectively when the mean hematocrit was 42.9 +/- 3.4 (+/- SD). For forensic purposes, it would be better to forgo making any conversion of a drug concentration measured in whole blood to that expected in plasma or serum; instead, therapeutic and toxic concentrations should be established for the actual specimens received.
Abstract: The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that Vmax/Km values in human liver microsomes were the highest for tofisopam, followed by tandospirone>clotiazepam>imipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5 microM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10 microM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform(s) of older drugs, for which metabolic profiles have not been reported.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: OBJECTIVE: The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. METHODS: Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. RESULTS: Mean omeprazole AUC (0,infinity) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. CONCLUSION: This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.
Abstract: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
Abstract: BACKGROUND: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. OBJECTIVE: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. METHODS: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. RESULTS: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised beta=0.229, p=0.04) as well as the duration of using AA drugs (standardised beta 0.231, p=0.032). CONCLUSION: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
Abstract: The three hydroxybenzodiazepines oxazepam, temazepam, and lorazepam used for their anxiolytic, sedative, and anticonvulsant properties are metabolized by glucuronidation, which is the predominant pathway in the clearance mechanism of exogenous and endogenous substances during phase II metabolism. The aim of this study was the synthesis of benzodiazepine-O-glucuronides as analytical reference substances. All benzodiazepines are prescribed clinically as racemic formulations. The resulting conjugates from the coupling reactions with glucuronic acid are epimeric pairs of glucuronides. Due to the importance of stereochemical factors in drug disposition it is necessary to separate the diastereomeric forms after synthesis. An enzyme-assisted synthesis was developed and optimized by using microsomal UGT from fresh swine liver to receive multimilligram amounts of the benzodiazepine glucuronides, which were not accessible by standard synthetic procedures, like the Koenigs-Knorr- and Williamson-ether-synthesis. Swine liver microsomes were prepared by homogenization and differential centrifugation of liver tissue. In the presence of liver microsomes the benzodiazepines and cofactor UDPGA were incubated for 24h. After incubation the microsomes were removed by protein precipitation and the residual benzodiazepines by liquid-liquid extraction (dichloromethane). The epimeric pairs of benzodiazepine glucuronides were separated by preparative high performance liquid chromatography (HPLC) followed by solid phase extraction (SPE) to obtain the pure benzodiazepine glucuronide epimers. The synthesis products were characterized by mass spectroscopy and nuclear magnetic resonance (NMR) spectroscopy.
Abstract: BACKGROUND/AIMS: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. METHODS: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). RESULTS: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. CONCLUSION: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.
Abstract: Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.