QT time prolongation
Adverse drug events
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Explanations of the substances for patients
The administration of ketoconazole and alprazolam should be avoided.
Elevated alprazolam concentrations - increased / prolonged sedationMechanism: The metabolism of alprazolam takes place to a large extent via the hepatic CYP system, especially via CYP3A4. Ketoconazole is a potent inhibitor of this isoenzyme.
Effect: According to the Swiss specialist information for alprazolam, simultaneous use with ketoconazole is contraindicated. Alprazolam AUC increased 3.19-fold following co-administration with ketoconazole in vivo.
Measures: The combination is to be avoided. If therapy with benzodiazepines is indicated for anxiolysis, a benzodiazepine should be selected from ketoconazole, the metabolism of which is less strongly mediated by CYP3A4 (e.g. lorazepam or oxazepam).
The administration of erythromycin and alprazolam should be avoided.
Elevated alprazolam concentrations - increased / prolonged sedationMechanism: The metabolism of alprazolam takes place to a large extent via the hepatic CYP system, especially via CYP3A4. Erythromycin is a moderate inhibitor of this isoenzyme, so inhibiting the breakdown of alprazolam could lead to an increase in the concentration of benzodiazepine.
Effect: Increased benzodiazepine concentrations can lead to significantly increased sedation and a prolongation of the sedating effect.
Measures: The combination is to be avoided. If therapy with benzodiazepines is indicated for anxiolysis, a benzodiazepine should be selected from erythromycin whose metabolism is less strongly mediated by CYP3A4 (e.g. lorazepam or oxazepam). If the combination is unavoidable, careful monitoring for signs of increased sedation must be carried out. A reduction in the alprazolam dose should be considered.
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. Erythromycin exposure increases to 239%, when combined with alprazolam (100%) and ketoconazole (239%). This can lead to increased side effects. Alprazolam exposure increases to 223%, when combined with erythromycin (155%) and ketoconazole (207%). This can lead to increased side effects. Ketoconazole exposure increases to 141%, when combined with erythromycin (141%) and alprazolam (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Erythromycin has a low oral bioavailability [ F ] of 24%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 2.3 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 73% and the volume of distribution [ Vd ] is 56 liters, which is why, with a mean hepatic extraction rate of 0.42, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via MRP2 and PGP.
Alprazolam has a high oral bioavailability [ F ] of 88%, which is why the maximum plasma levels [Cmax] tend to change little during an interaction. The terminal half-life [ t12 ] is 11.7 hours and constant plasma levels [ Css ] are reached after approximately 46.8 hours. The protein binding [ Pb ] is moderately strong at 70.2% and the volume of distribution [ Vd ] is 50 liters in the middle range, Since the substance has a low hepatic extraction rate of 0.04, displacement from protein binding [Pb] in the context of an interaction can increase exposure. The metabolism mainly takes place via CYP3A4.
Ketoconazole has a mean oral bioavailability [ F ] of 67%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 5 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 91.5% and the volume of distribution [ Vd ] is very large at 84 liters, Since the substance has a low hepatic extraction rate of 0.09, displacement from protein binding [Pb] in the context of an interaction can increase exposure. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø||Ø|
Rating: According to our knowledge, neither erythromycin, alprazolam nor ketoconazole increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Rating: According to our findings, neither erythromycin, alprazolam nor ketoconazole increase anticholinergic activity.
QT time prolongation
Rating: In combination, erythromycin and ketoconazole can potentially trigger ventricular arrhythmias of the torsades de pointes type. We do not know of any QT-prolonging potential for alprazolam.
General adverse effects
|Side effects||∑ frequency||ery||alp||ket|
|Coordination problem||24.8 %||n.a.||24.8↑||n.a.|
|Memory impairment||24.3 %||n.a.||24.3↑||n.a.|
|Increased appetite||19.9 %||n.a.||19.9↑||n.a.|
|Weight gain||14.9 %||n.a.||14.9↑||n.a.|
Xerostomia (12.4%): alprazolam
Nausea (2%): erythromycin, ketoconazole
Vomiting (2%): erythromycin, ketoconazole
Abdominal pain: erythromycin
Loss of appetite: erythromycin
Clostridium difficile diarrhea: erythromycin
Depression (11.7%): alprazolam
Rebound effect: alprazolam
Reduced libido (10.2%): alprazolam
Confusion (6%): alprazolam
Burning sensation: ketoconazole
Stevens johnson syndrome: erythromycin, alprazolam
Toxic epidermal necrolysis: erythromycin
Adrenal insufficiency: ketoconazole
Hearing loss: erythromycin
Ventricular arrhythmia: erythromycin, ketoconazole
Cholestatic hepatitis: erythromycin
Liver failure: erythromycin, alprazolam
Allergic skin reactions like pruritus and rash: erythromycin
Hypersensitivity reaction: ketoconazole
Tubulointerstitial nephritis: erythromycin
Based on your
Abstract: No Abstract available
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: No Abstract available
Abstract: No Abstract available
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: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Abstract: OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo. METHOD: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. CONCLUSION: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.
Abstract: Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.
Abstract: We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CL(int)) for 4-hydroxylation and CYP3A4 content and between the CL(int) for alpha-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CL(int) for CYP3A4 was about 2-fold higher than the CL(int) for CYP3A5 in the case of 4-hydroxylation. However, the CL(int) for CYP3A5 was about 3-fold higher than the CL(int) for CYP3A4 in the case of alpha-hydroxylation. The metabolic rates for 4- and alpha-hydroxylation increased as the added amount of cytochrome b(5) increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b(5). The values of CL(int), in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CL(int) value (sum of 4- and alpha-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitro K(i) values and reported pharmacokinetic parameters of ketoconazole was 2.30-2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73-1.79 vs 1.58-1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants.
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: Ketoconazole is not known to be proarrhythmic without concomitant use of QT interval-prolonging drugs. We report a woman with coronary artery disease who developed a markedly prolonged QT interval and torsades de pointes (TdP) after taking ketoconazole for treatment of fungal infection. Her QT interval returned to normal upon withdrawal of ketoconazole. Genetic study did not find any mutation in her genes that encode cardiac IKr channel proteins. We postulate that by virtue of its direct blocking action on IKr, ketoconazole alone may prolong QT interval and induce TdP. This calls for attention when ketoconazole is administered to patients with risk factors for acquired long QT syndrome.
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: OBJECTIVE: The antifungal drug ketoconazole (KTZ) is known as an inhibitor of, especially, the CYP3A subfamily, which catalyzes the metabolism of a large variety of drugs. Interactions between KTZ and CYP3A substrates have been reported both in vivo and in vitro. Most of them, however, involved the KTZ racemate. KTZ racemate and the separate enantiomers, 2R,4R; 2R,4S; 2S,4S, and 2S,4R, were evaluated for their selectivity in inhibiting alprazolam and quinine metabolism. METHODS: The inhibition of alprazolam and quinine metabolism was studied in an in vitro system of human liver microsomes (HLM), recombinant of CYP3A4 and CYP3A5. The concentrations of formed 3-hydroxyquinine and 4- and alpha-hydroxyalprazolam were measured by HPLC and LC-MS, respectively. RESULTS: Quinine 3-hydroxylation was catalyzed to a similar extent by CYP3A4 and CYP3A5. The formation rate of 4-hydroxyalprazolam was higher than that of alpha-hydroxyalprazolam for each HLM, CYP3A4 and CYP3A5. KTZ racemate and enantiomers showed differential inhibitory effects of quinine and alprazolam metabolism. Quinine metabolism catalyzed by HLM, CYP3A4 and CYP3A5 was potently inhibited by the trans-enantiomer KTZ 2S,4S, with IC(50) value of 0.16 microM for HLM, 0.04 microM for CYP3A4 and 0.11 microM for CYP3A5. The same enantiomer showed the lowest IC(50) values of 0.11 microM for HLM and 0.04 microM for CYP3A5 with respect to alprazoalm 4-hydroxylation and also the same pattern for alprazolamalpha-hydroxylation, 0.13 microM for HLM and 0.05 microM for CYP3A5. Alprazolam metabolism (both alpha- and 4- hydroxylations) catalyzed by CYP3A4 was inhibited potently by the cis-enantiomer KTZ 2S,4R, with IC(50) values of 0.03 microM. CONCLUSIONS: Alprazolam and quinine metabolism is catalyzed by both CYP3A4 and CYP3A5. The present study showed that different KTZ enantiomers inhibit CYP3A4 and CYP3A5 to different degrees, indicating that structural differences among the enantiomers would be related to their inhibitory potency on these two enzymes.
Abstract: OBJECTIVE: To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients. METHODS: Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16. RESULTS: Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. C(max) and AUC(0-24) were significantly decreased by 44 and 72%, respectively. The T ((1/2)) was significantly shorter by 58%. CONCLUSION: Efavirenz has a strong inducing effect on the metabolism of ketoconazole.
Abstract: AIMS: To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. METHODS: Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. RESULTS: Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. CONCLUSIONS: The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
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: All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.