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
L'administration de itraconazole et de alprazolam doit être évitée.
Concentrations élevées d'alprazolam - sédation accrue / prolongéeMécanisme: Le métabolisme de l'alprazolam s'effectue dans une large mesure via le système hépatique CYP, en particulier via le CYP3A4. L'itraconazole est un puissant inhibiteur de cette isoenzyme, de sorte que l'inhibition de la dégradation de l'alprazolam pourrait entraîner une augmentation de la concentration de benzodiazépine.
Effet: selon les informations du spécialiste suisse de l'alprazolam, l'utilisation simultanée d'itraconazole est contre-indiquée. Une étude avec l'itraconazole a entraîné une augmentation significative de l'ASC d'une dose unique d'alprazolam et une augmentation de la demi-vie d'élimination.
Mesures: La combinaison est à éviter. Si un traitement par benzodiazépines est indiqué pour l'anxiolyse, une benzodiazépine doit être choisie parmi l'itraconazole, dont le métabolisme est moins fortement médié par le CYP3A4 (par exemple, le lorazépam ou l'oxazépam).
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. L'exposition à la alprazolam augmente à 204%, lorsqu'il est associé à la cimétidine (124%) et à la itraconazole (197%). Cela peut entraîner une augmentation des effets secondaires. 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 itraconazole. L'exposition à la itraconazole augmente à 110%, lorsqu'il est associé à la alprazolam (100%) et à la cimétidine (110%).
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 itraconazole a une biodisponibilité orale moyenne [ F ] de 55%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est de 21 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est très forte à 99.8% et le volume de distribution [ Vd ] est très important à 796 litres, c'est pourquoi, à un taux d'extraction hépatique moyen de 0,9, le débit sanguin hépatique [Q] et une modification de la liaison aux protéines [Pb] sont pertinents. Le métabolisme s'effectue principalement via le CYP3A4 et le transport actif se fait notamment via PGP.
|Les scores||∑ Points||alp||cim||itr|
|Effets sérotoninergiques a||0||Ø||Ø||Ø|
Évaluation: Selon nos connaissances, ni la alprazolam, cimétidine ni la itraconazole n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||alp||cim||itr|
|Kiesel & Durán b||1||Ø||+||Ø|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à des doses dans l'intervalle thérapeutique supérieur.
Évaluation: La cimétidine n'a qu'un effet léger sur le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la posologie se situe dans la plage habituelle. Selon nos résultats, ni la alprazolam ni la itraconazole n'augmentent l'activité anticholinergique.
Extension de temps QT
|Les scores||∑ Points||alp||cim||itr|
Évaluation: En association, la cimétidine et la itraconazole peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes. Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la alprazolam.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||alp||cim||itr|
|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 %||14.9↑||n.a.||n.a.|
Xérostomie (12.4%): alprazolam
La nausée (7%): itraconazole
Vomissements (5%): itraconazole
Douleur abdominale (2.9%): itraconazole
La diarrhée (2.9%): itraconazole
Pancréatite: cimétidine, itraconazole
La dépression (11.7%): alprazolam
Effet de rebond: alprazolam
Diminution de la libido (10.2%): alprazolam
Rhinopharyngite (9%): itraconazole
Infection respiratoire supérieure (8%): itraconazole
Sinusite (4.5%): itraconazole
Œdème pulmonaire: itraconazole
Mal de crâne (6.1%): itraconazole
Confusion (6%): alprazolam
Démangeaison de la peau (6%): itraconazole
Prurit (4%): itraconazole
Syndrome de Stevens-Johnson: alprazolam
Gynécomastie (4%): cimétidine
Œdème périphérique (4%): itraconazole
Hypertension (3%): itraconazole
Insuffisance cardiaque: itraconazole
Fièvre (2.5%): itraconazole
Insuffisance hépatique: alprazolam
Perte auditive: itraconazole
Réaction d'hypersensibilité: itraconazole
Sur la base de vos
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: 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: No Abstract available
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: To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200 mg/day or matched placebo orally for 6 days took an oral 0.8 mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48 h after alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersøgelser side effect rating scale. Itraconazole significantly (P < 0.01) increased the area under the concentration-time curves from 0 h to infinity (252 +/- 47 versus 671 +/- 205 ng h/ml), decreased the apparent oral clearance (0.89 +/- 0.21 versus 0.35+/-0.10 ml/min per kg) and prolonged the elimination half-life (15.7 +/- 4.1 versus 40.3 +/- 13.5 h) of alprazolam. The test performed during itraconazole treatment showed significantly depressed psychomotor function. It is suggested that itraconazole, a potent CYP3A4 inhibitor, increases plasma concentration of alprazolam via its inhibitory effects on alprazolam metabolism. Thus, this study supports previous studies suggesting that CYP3A4 is the major enzyme catalyzing the metabolism of alprazolam. Enhanced side effects of alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes.
Abstract: Cytochrome P450(CYP)3A4 is one of the CYP enzymes catalyzing oxidative metabolism, and involved in the metabolism of many drugs. Among benzodiazepines, alprazolam, triazolam, brotizolam and midazolam are mainly metabolished by CYP3A4, and quazepam, diazepam and flunitrazepam are partly metabolised by this enzyme. Azole antifungals, macrolide antibiotics, calcium antagonists and grapefruit juice inhibit CYP3A4 activity, while antiepileptics and rifampicin induce the activity. The drugs affecting CYP3A4 activity inhibit or induce the metabolism of the benzodiazepines metabolised by this enzyme, and induce side effects or reduce therapeutic effects of these drugs. Therefore, the combination of the two groups of drugs should be avoided, and if it is unavoidable the dose of benzodiazepines should be adjusted.
Abstract: Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.
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: 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: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: PURPOSE: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. METHOD: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. RESULTS: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. CONCLUSION: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
Abstract: This article reviews in vitro metabolic and in vivo pharmacokinetic drug-drug interactions of nine antifungal agents: six azoles (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) and three echinocandins (anidulafungin, caspofungin, and micafungin). In in vitro interaction studies, itraconazole, ketoconazole, and miconazole were found to have higher inhibitory effects on cytochrome P450 (P450 or CYP) 3A4 and 3A5 activities than the other azoles or echinocandins did. Fluconazole, itraconazole, and voriconazole were relatively less potent inhibitors of CYP3A5 than of CYP3A4. The inhibitory effects of fluconazole, itraconazole, ketoconazole, and voriconazole against CYP3A4 and CYP3A5 seemed to be correlated with their dissociation constants for CYP51 (lanosterol 14α-demethylase) from Candida albicans. In in vivo pharmacokinetic studies, itraconazole was found to be a potent clinically important inhibitor of CYP3A4/5 substrates, and fluconazole and voriconazole increased the blood/plasma concentrations of not only CYP3A4/5 substrates but also CYP2C9 substrates. Miconazole was a potent inhibitor of all P450s investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. For the echinocandins, no marked inhibition of P450 activities, except for some inhibition of CYP3A4/5 activity, was observed in vitro. The blood/plasma concentrations of concomitant drugs were not markedly affected by coadministration of echinocandins in vivo, suggesting that echinocandins do not cause clinically significant interactions with drugs that are metabolized by P450s via the inhibition of metabolism. The differential effects of these antifungal agents on P450 activities must be considered when clinicians select antifungal agents for patients also receiving other drugs.
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.