Extension de temps QT
Effets indésirables des médicaments
Variantes ✨Pour l'évaluation intensive en calcul des variantes, veuillez choisir l'abonnement standard payant.
Explications pour les patients
|Carbamazépine||1.25 [1.25,2.08] 1||1||1.25|
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. L'exposition à la alprazolam est réduite à 40%, lorsqu'il est associé à la cimétidine (118%) et à la carbamazépine (38%). Cela peut être associé à une efficacité réduite. Nous n'avons détecté aucune modification de l'exposition à la cimétidine. Nous ne pouvons actuellement pas estimer l'influence de la alprazolam et de la carbamazépine. L'exposition à la carbamazépine augmente à 125%, lorsqu'il est associé à la alprazolam (100%) et à la cimétidine (125%). L'ASC est comprise entre 125% et 208% selon le
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La alprazolam a une biodisponibilité orale élevée [ F ] de 88%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à peu changer pendant une interaction. La demi-vie terminale [ t12 ] est de 11.7 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est modérément forte à 70.2% et le volume de distribution [ Vd ] est de 50 litres dans la fourchette moyenne, Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Le métabolisme s'effectue principalement via le CYP3A4.
La cimétidine a une biodisponibilité orale moyenne [ F ] de 65%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 1.6333333 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est très faible à 19% et le volume de distribution [ Vd ] est très important à 91 litres. Le métabolisme ne se fait pas via les cytochromes communs et le transport actif s'effectue en partie via BCRP et PGP.
La carbamazépine a une biodisponibilité orale moyenne [ F ] de 78%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est de 20 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est modérément forte à 77.2% et le volume de distribution [ Vd ] est très important à 90 litres, Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Le métabolisme a lieu via le CYP1A2, CYP2C8, CYP2C9 et le CYP3A4, entre autres.
|Les scores||∑ Points||alp||cim||car|
|Effets sérotoninergiques a||0||Ø||Ø||Ø|
Évaluation: Selon nos connaissances, ni la alprazolam, cimétidine ni la carbamazépine n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||alp||cim||car|
Recommandation: Le risque d'effets secondaires anticholinergiques tels que vision trouble, confusion et tremblements est augmenté avec ce traitement. Si possible, la thérapie doit être modifiée ou le patient doit être étroitement surveillé pour d'autres symptômes tels que La constipation, la mydriase et la vigilance réduite sont surveillées.
Évaluation: Ensemble, la cimétidine (modérer), carbamazépine (modérer) et la alprazolam (Bénin) augmentent l'activité anticholinergique.
Extension de temps QT
|Les scores||∑ Points||alp||cim||car|
Recommandation: Veuillez vous assurer que les facteurs de risque influençables sont minimisés. Les perturbations électrolytiques telles que de faibles niveaux de calcium, de potassium et de magnésium doivent être compensées. La dose efficace la plus faible de cimétidine doit être utilisée.
Évaluation: La cimétidine peut potentiellement prolonger le temps QT et s'il existe des facteurs de risque, les arythmies de type torsades de pointes peuvent être favorisées. Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la alprazolam et la carbamazépine.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||alp||cim||car|
|Problème de coordination||24.8 %||24.8↓||n.a.||n.a.|
|Déficience de mémoire||24.3 %||24.3↓||n.a.||n.a.|
|Augmentation de l'appétit||19.9 %||19.9↓||n.a.||n.a.|
Gain de poids (14.9%): alprazolam
Gynécomastie (4%): cimétidine
Xérostomie (13.3%): carbamazépine, alprazolam
La nausée (8%): carbamazépine
Vomissements (8%): carbamazépine
La dépression (11.7%): alprazolam
Effet de rebond: alprazolam
Diminution de la libido (10.2%): alprazolam
Réactions cutanées allergiques (10%): carbamazépine
Syndrome de Stevens-Johnson: carbamazépine, alprazolam
Nécrolyse épidermique toxique: carbamazépine
Confusion (6%): alprazolam
Vision floue (5.5%): carbamazépine
Leucopénie (2%): carbamazépine
Bloc auriculo-ventriculaire: carbamazépine
Œdème périphérique: carbamazépine
Hépatite cholestatique: carbamazépine
Syndrome de disparition des voies biliaires: carbamazépine
Insuffisance hépatique: alprazolam
Réaction d'hypersensibilité: carbamazépine
Néphrite tubulo-interstitielle: carbamazépine
Sur la base de vos
Abstract: The interaction between fluoxetine and carbamazepine was investigated in six normal, healthy male volunteers (aged 23 to 40 years). Subjects were given carbamazepine, 400 mg every morning, for 3 weeks. Venous carbamazepine blood samples were obtained at baseline and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the morning dose. Fluoxetine, 20 mg every morning, was then coadministered with carbamazepine for 7 days. Venous carbamazepine blood samples were again obtained as described. Carbamazepine and carbamazepine-10,11-epoxide (CBZE) were assayed by HPLC. Addition of fluoxetine resulted in a significant increase in the area under the concentration-time curve of carbamazepine (105.93 +/- 18.05 micrograms/ml.hr versus 134.97 +/- 12.15 micrograms/ml.hr; t = 3.284; df = 5; p = 0.022) and CBZE (11.6 +/- 1.93 micrograms/ml.hr versus 15.2 +/- 2.4 micrograms/ml.hr; t = 2.805; df = 5; p = 0.038). Both oral and intrinsic clearance of carbamazepine was decreased significantly on fluoxetine addition (3.87 +/- 0.68 L/hr versus 2.98 +/- 0.26 L/hr; t = 3.025; df = 5; p = 0.029 and 17.90 +/- 4.9 L/hr versus 11.92 +/- 1.4 L/hr; t = 3.037; df = 5; p = 0.029, respectively). No significant changes were determined for fraction of absorbed dose, volume of distribution, absorption rate constant, and elimination rate constant. These findings suggest that fluoxetine can inhibit the metabolism of carbamazepine. Careful monitoring of patients is recommended when these two drugs are coadministered.
Abstract: Alprazolam is a short-acting triazolobenzodiazepine with anxiolytic and antidepressant properties. It has a half-life of 10-15 hours after multiple oral doses. Approximately 20% of an oral dose is excreted unchanged in the urine. The major urinary metabolites are alpha-OH alprazolam glucuronide and 3-HMB benzophenone glucuronide. The objective of this study was to characterize the reactivity of alprazolam and three metabolites in the Abbott ADx and TDx urinary benzodiazepine assays compared with the EMIT d.a.u. benzodiazepine assay. Alprazolam (at 300 ng/mL) gave an equivalent response as the 300 ng/mL low control (nordiazepam). alpha-OH alprazolam gave an equivalent response to this control between 300-500 ng/mL and 4-OH alprazolam between 500-1000 ng/mL. The 3-HMB benzophenone was not positive even at 10,000 ng/mL. The ADx screening assay was positive in 26 of 31 urine specimens collected from alprazolam-treated patients. All 31 of these specimens were confirmed positive for alpha-OH alprazolam by GC/MS after enzymatic hydrolysis and formation of a TMS derivative. For the TDx, 27 of 31 specimens were positive for benzodiazepines and all 31 were confirmed by GC/MS. All 5 of the negative ADx specimens and 4 of 5 TDx specimens contained 150-400 ng/mL of alpha-OH alprazolam. In conclusion, both the ADx and TDx urine benzodiazepine assays are acceptable screening assays for alprazolam use when the alpha-OH alprazolam concentration is greater than 400 ng/mL.
Abstract: Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.
Abstract: Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.
Abstract: A number of drugs inhibit the metabolism of carbamazepine catalyzed by cytochrome P450, sometimes resulting in carbamazepine intoxication. However, there is little information available concerning the identity of the specific isoforms of P450 responsible for the metabolism of this drug. This study addressed the role of CYP3A4 in the formation of carbamazepine-10,11-epoxide, the major metabolite of carbamazepine. Results of the study showed that: (1) purified CYP3A4 catalyzed 10,11-epoxidation; (2) cDNA-expressed CYP3A4 catalyzed 10,11-epoxidation (Vmax = 1730 pmol/min/nmol P450, Km = 442 microM); (3) the rate of 10,11-epoxidation correlated with CYP3A4 content in microsomes from sixteen human livers (r2 = 0.57, P < 0.001); (4) triacetyloleandomycin and anti-CYP3A4 IgG reduced 10,11-epoxidation to 31 +/- 6% (sixteen livers) and 43 +/- 2% (four livers) of control rates, respectively; and (5) microsomal 10,11-epoxidation but not phenol formation was activated 2- to 3-fold by alpha-naphthoflavone and progesterone and by carbamazepine itself (substrate activation). These findings indicate that CYP3A4 is the principal catalyst of 10,11-epoxide formation in human liver. Experiments utilizing a panel of P450 isoform selective inhibitors also suggested a minor involvement of CYP2C8 in liver microsomal 10,11-epoxidation. Epoxidation by CYP2C8 was confirmed in incubations of carbamazepine with cDNA-expressed CYP2C8. The role of CYP3A4 in the major pathway of carbamazepine elimination is consistent with the number of inhibitory drug interactions associated with its clinical use, interactions that result from a perturbation of CYP3A4 catalytic activity.
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: BACKGROUND: St John's Wort is a popular herbal product used by approximately 7% of patients with epilepsy. Previous reports have described reductions in concentrations of CYP3A4 substrates indinavir and cyclosporine (INN, ciclosporin) associated with St John's Wort. OBJECTIVE: Our objective was to determine the effect of St John's Wort on steady state carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics. METHODS AND SUBJECTS: Eight healthy volunteers (5 men; age range, 24-43 years) participated in this unblinded study. Subjects received 100 mg of carbamazepine twice daily for 3 days, 200 mg twice daily for 3 days, and then 400 mg once daily for 14 days. Blood samples were collected before and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the dose on day 21. The subjects then took 300 mg of St John's Wort (0.3% hypericin standardized tablet) 3 times daily with meals and with carbamazepine for 14 days. On day 35, blood sampling was repeated. Plasma samples were analyzed for carbamazepine and carbamazepine-10,11-epoxide with HPLC. We compared carbamazepine and carbamazepine-10,11-epoxide noncompartmental pharmacokinetic parameter values before and after St John's Wort with a paired Student t test. RESULTS: We found no significant differences before or after the administration of St John's Wort in carbamazepine peak concentration (7.2 +/- 1 mg/L before versus 7.6 +/- 1.3 mg/L after), trough concentration (4.8 +/- 0.5 mg/L before versus 4.3 +/- 0.8 mg/L after), area under the plasma concentration-time curve (142.4 +/- 12.9 mg x h/L before versus 143.8 +/- 27.2 mg x h/L after), or oral clearance (2.8 +/- 0.3 L/h before versus 2.9 +/- 0.6 L/h after). Similarly, no differences were found in peak concentration (2 +/- 0.5 mg/L before versus 2.1 +/- 0.4 mg/L after), trough concentration (1.3 +/- 0.3 mg/L before versus 1.4 +/- 0.3 mg/L after), and area under the plasma concentration-time curve (37.5 +/- 7.4 mg x h/L before versus 41.9 +/- 10.3 mg x h/L after) of carbamazepine-10,11-epoxide. CONCLUSIONS: The results suggest that treatment with St John's Wort for 14 days did not further induce the clearance of carbamazepine.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.
Abstract: BACKGROUND: Roughly 20% of patients in hospital have impaired kidney function. This is frequently overlooked because of the creatinine-blind range in which early stages of renal failure are often hidden. Chronic kidney disease is divided into 5 stages (CKD 1 to 5). METHODS: Selective literature search. RESULTS: Methotrexate, enoxaparin and metformin are examples of drugs that should no longer be prescribed if the glomerular filtration rate (GFR) is 60 mL/min or less. With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. atenolol) or anticonvulsive (e.g. gabapentin) drugs, the advice is to use alternative preparations such as gliquidone, metoprolol or carbamazepine which are independent of kidney function. Drug dose adjustment should be considered with antimicrobial (e.g. ampicillin, cefazolin), antiviral (e.g. aciclovir, oseltamivir) and, most recently, also for half of all chemotherapeutic and cytotoxic drugs in patients with impaired kidney function (with e.g. cisplatin, for instance, but not with paclitaxel). CONCLUSION: Decisions concerning drug dose adjustment must be based on the pharmacokinetics but this is an adequate prerequisite only in conjunction with the pharmacodynamics. There are two different dose adjustment rules: proportional dose reduction according to Luzius Dettli, and the half dosage rule according to Calvin Kunin. The latter leads to higher trough concentrations but is probably more efficient for anti-infective therapy.
Abstract: Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half-life in patients at steady state have not been determined. We developed an intravenous, stable-labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety-two patients received a 100-mg infusion of SL-carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography-mass spectrometry, and concentration-time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half-life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.
Abstract: To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 22.214.171.124 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r=0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT-1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs.
Abstract: The aim of the present study was to investigate the distribution ofvariantsand, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). Theandpolymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose incarriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39. 15.46 ± 4.35 mg/kg;= 0.5]. Dose-normalized serum concentration of carbamazepine was higher in(mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL,= 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only innon carriers (r = 0.52,= 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect ofpolymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that thepolymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.
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: 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.