QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of meperidine and diazepam. Please also consult the relevant specialist information.
|Diazepam||1 [0.83,1.53] 1||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for meperidine, when combined with diazepam (100%). We do not expect any change in exposure for diazepam, when combined with meperidine (100%). The AUC is between 83% and 153% depending on the CYP2C19
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Meperidine has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 5.9 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 70% and the volume of distribution [ Vd ] is very large at 336 liters, which is why, with a mean hepatic extraction rate of 0.47, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism takes place via CYP2B6, CYP2C19 and CYP3A4, among others.
Diazepam has a mean oral bioavailability [ F ] of 76%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 36 hours and constant plasma levels [ Css ] are only reached after more than 144 hours. The protein binding [ Pb ] is 97% strong and the volume of distribution [ Vd ] is very large at 83 liters. Since the substance has a low hepatic extraction rate of 0.03, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2B6, CYP2C19 and CYP3A4, among others.
|Serotonergic Effects a||2||++||Ø|
Recommendation: As a precautionary measure, symptoms of serotonergic overstimulation should be taken into account, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Meperidine modulates the serotonergic system to a moderate extent. The risk of a serotonergic syndrome can be classified as low with this medication if the dosage is in the usual range. According to our knowledge, diazepam does not increase serotonergic activity.
|Kiesel & Durán b||3||++||+|
Recommendation: The risk of anticholinergic side effects such as blurred vision, confusion and tremor is increased with this therapy. If possible, the therapy should be switched or the patient should be closely monitored for other symptoms, such as constipation, mydriasis and reduced vigilance.
Rating: Together, meperidine (moderate) and diazepam (mild) increase anticholinergic activity.
QT time prolongation
We do not know of any QT-prolonging potential for meperidine and diazepam.
General adverse effects
|Side effects||∑ frequency||mep||dia|
|Rebound effect||1.0 %||n.a.||+|
Seizure: diazepam, meperidine
Raised intracranial pressure: meperidine
Cardiac arrest: meperidine
Cardiogenic shock: meperidine
Orthostatic hypotension: meperidine
Respiratory depression: diazepam, meperidine
Respiratory arrest: meperidine
Adrenal insufficiency: meperidine
Hypersensitivity reaction: meperidine
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
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: The effect of concurrent cimetidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (18-31 years). The subjects received 70 mg i.v. pethidine HCl doses before and during cimetidine treatment (1200 mg/day p.o.). During cimetidine treatment, pethidine total body clearance (CL) decreased by 22% (0.611 +/- 0.101 [mean +/- s.d.] to 0.474 +/- 0.098 1 kg-1 h, P less than 0.05) and pethidine volume of distribution at steady state (Vss) decreased by 13% (4.79 +/- 0.82 to 4.16 +/- 0.75 l/kg, P less than 0.05). A cimetidine-induced reduction in pethidine oxidation to norpethidine was suggested by a 23% reduction in norpethidine area under the curve from 0 to 24 h (472 +/- 93 to 362 +/- 38 ng ml-1 h, P less than 0.05) and a 29% reduction in peak norpethidine concentration (26.7 +/- 5.3 to 18.9 +/- 1.9 ng/ml, P less than 0.05). There were no significant linear correlations of serum trough cimetidine concentration with percentage reductions in pethidine CL, pethidine Vss, norpethidine AUC (24), or norpethidine peak concentrations. It would appear that the cimetidine-pethidine kinetic interaction may be of sufficient magnitude to be clinically significant. Caution is advised when patients are treated concurrently with these two agents.
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: In order to evaluate the anticholinergic effect of fentanyl and pethidine, the influence of these drugs on the cumulative dose-response curves of carbacholine on the guinea-pig ileum has been investigated. Fentanyl and pethidine displaced the dose-response curve for carbacholine to the right in a parallel fashion, indicating competitive antagonism. Dissociation constants determined by an agonist EC versus antagonist plot were 0.22 mumol/l for fentanyl and 1.4 mumol/l for pethidine. It is concluded that during high-dose fentanyl anaesthesia, fentanyl may bind to muscarinic receptors and thereby produce a central anticholinergic syndrome. An additional finding was that the maximal response to carbacholine increased significantly when combined with pethidine.
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: Meperidine was initially synthesized as an anticholinergic agent but was soon discovered to have analgesic properties. Although meperidine's anticholinergic effects were demonstrated in vivo, the anticholinergic effects on the biliary and renal tracts have not been demonstrated in vivo. Studies have clearly demonstrated that meperidine is no more efficacious in treating biliary or renal tract spasm than comparative mu opioids. The initial studies demonstrating the analgesic efficacy of meperidine were mostly case reports and not double-blind, randomized, controlled trials in specific populations. Subsequent comparative studies failed to demonstrate any advantages of meperidine over comparable doses of other analgesics. Meperidine was portrayed in practice and teaching as having unique clinical advantages. The analgesic effects of meperidine are not pronounced, and, in addition, meperidine use is complicated by unique side effects including serotonergic crisis and normeperidine toxicity. Meperidine's poor efficacy, toxicity, and multiple drug interactions have resulted in a movement to replace meperidine with more efficacious and less toxic opioid analgesics.
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: Physiologically based pharmacokinetic (PBPK) models can be used to predict drug disposition in humans from animal data and the influence of disease or other changes in physiology on the pharmacokinetics of a drug. The potential usefulness of a PBPK model must however be balanced against the considerable effort needed for its development. Proposed methods to simplify PBPK modeling include predicting the necessary tissue:blood partition coefficients (kp) from physicochemical data on the drug instead of determining them in vivo, formal lumping of model compartments, and replacing the various kp values of the organs and tissues by only two values, for "fat" and "lean" tissues, respectively. The aim of this study was to investigate the effects of simplifying complex PBPK models on their ability to predict drug disposition in humans. Arterial plasma concentration curves of fentanyl and pethidine were simulated by means of a number of successively reduced models. Median absolute prediction errors were used to evaluate the performance of each model, in relation to arterial plasma concentration data from clinical studies, and the Wilcoxon matched pairs test was used for comparison of predictions. An originally diffusion-limited model for fentanyl was simplified to perfusion-limitation, and this model was either lumped, reducing 11 organ/tissue compartments to six, or changed to a model based on only two kp values, those of fat (used for fat and lungs) and muscle (used for all other tissues). None of these simplifications appreciably changed the predictions of arterial drug concentrations in the 10 patients. Perfusion-limited models for pethidine were set up using either experimentally determined [Gabrielsson et al. 1986] or theoretically calculated [Davis and Mapleson 1993] kp values, and predictions using the former were found to be significantly better. Lumping of the models did not appreciably change the predictions; however, going from a full set of kp values to only two ("fat" and "lean") had an adverse effect. Using a kp for lungs determined either in rats or indirectly in humans [Persson et al. 1988], i.e., a total of three kp values, improved these predictions. In conclusion, this study strongly suggested that complex PBPK models for lipophilic basic drugs may be considerably reduced with marginal loss of power to predict standard plasma pharmacokinetics in humans. Determination of only two or three kp values instead of a "full" set can mean an important reduction of experimental work to define a basic model. Organs of particular pharmacological or toxicological interest should of course be investigated separately as needed. This study also suggests and applies a simple method for statistical evaluation of the predictions of PBPK models.
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: Meperidine is an opioid analgesic metabolized in the liver by N-demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S-mephenytoin N-demethylation (r = 0.88, p < 0.0001 at 75 > microM meperidine, and r = 0.89, p < 0.0001 at 350 microM meperidine, n = 21) and CYP3A4-selective midazolam 1'-hydroxylation (r = 0.59, p < 0.01 at 75 microM meperidine, and r = 0.55, p < 0.01 at 350 microM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S-mephenytoin 4'-hydroxylation (r = 0.36, p = 0.2 at 75 microM meperidine, and r = 0.02, p = 0.9 at 350 microM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19.
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: 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 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.