Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin

Quinney, Sara K.; Malireddy, S. R.; Vuppalanchi, Raj; Hamman, Mitchell A.; Chalasani, Naga; Gorski, J. Christopher; Hall, Stephen D.

doi:10.1007/s00228-012-1339-x

Cited by 26 publications

(20 citation statements)

References 40 publications

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“…As such, the extent of in vivo CYP3A inhibition with clarithromycin does not approach what could be considered maximal . As a time‐dependent inhibitor , the onset and offset of CYP3A inhibition is likely to be delayed . In a study of erythromycin – also a macrolide derivative producing time‐dependent CYP3A inhibition – the apparent half‐life of onset of inhibition following initiation of treatment was calculated to be 22.5 h .…”

Section: Discussionmentioning

confidence: 99%

“…As such, the extent of in vivo CYP3A inhibition with clarithromycin does not approach what could be considered maximal [4,8,67]. As a time-dependent inhibitor [62][63][64][65][66][71][72][73][74], the onset and offset of CYP3A inhibition is likely to be delayed [75]. In a study of erythromycinalso a Figure 1 Ratios of total area under the curve (AUC) for oral midazolam during coadministration of each of four inhibitors divided by AUC in the control condition with no inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Greenblatt

Harmatz

2015

Brit J Clinical Pharma

119

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AIMSThe regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. METHODSThe biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (R AUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. RESULTSMean (± SE) R AUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). R AUC values were not significantly related to inhibitor dosage or to duration of inhibitor preexposure prior to administration of MDZ. CONCLUSIONSRitonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Greenblatt

Harmatz

2015

Brit J Clinical Pharma

119

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“…Examples of reversible CYP inhibitors used experimentally and clinically include: ketoconazole and ritonavir for CYP3A, quinidine for CYP2D6, fluvoxamine for CYP1A2 and CYP2C19, clopidogrel for CYP2B6, and sulfaphenazole for CYP2C9. In the case of mechanism‐based inhibition (MBI)—also termed time‐dependent inhibition—the inhibitory chemical binds to the active site of the enzyme and itself is metabolized to a product that irreversibly inactivates the enzyme . Clinical recovery from MBI may be somewhat slower compared to reversible inhibition, since restoration of metabolic activity depends on the intrinsic rate of enzyme synthesis and regeneration.…”

Section: Mechanisms Of Drug Interactions: Inhibition and Inductionmentioning

confidence: 99%

“…In the case of mechanismbased inhibition (MBI)-also termed time-dependent inhibition-the inhibitory chemical binds to the active site of the enzyme and itself is metabolized to a product that irreversibly inactivates the enzyme. [8][9][10][11][12][13] Clinical recovery from MBI may be somewhat slower compared to reversible inhibition, since restoration of metabolic activity depends on the intrinsic rate of enzyme synthesis and regeneration. Examples of entities reported to produce MBI include a number of the macrolide antimicrobials (erythromycin, clarithromycin), paroxetine, ritonavir, gestodene, verapamil, and furanocoumarin derivatives contained in grapefruit juice.…”

Section: Mechanisms Of Drug Interactions: Inhibition and Inductionmentioning

confidence: 99%

Mechanisms and Consequences of Drug‐Drug Interactions

Greenblatt

2017

Clinical Pharm in Drug Dev

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Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins. These DDIs can be complex and time-dependent in nature. Because time and resources available for new drug development are necessarily limited, not all potential DDIs can be evaluated via clinical pharmacokinetic studies in the course of development of HIV, HCV, and substance abuse treatments. Strategies are needed to refine existing in vitro models and screening techniques to allow more efficient targeting of resources to those clinical studies having the highest impact in terms of enhancing medication effectiveness and patient safety.

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“…Modifications included use of plasma (instead of urine) caffeine and dextromethorphan concentrations, different sample collection times for some probes, and evaluation of different pharmacokinetic parameters, including parent/metabolite ratios. The latter endpoints have been previously used as a measure of various CYP activities . In addition, the effect of steady‐state etravirine on the pharmacokinetics of single‐dose digoxin in healthy subjects was investigated in a separate study.…”

mentioning

confidence: 99%

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

Kakuda

Solingen-Ristea

Onkelinx

et al. 2013

The Journal of Clinical Pharmacology

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The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.

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Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin

Cited by 26 publications

References 40 publications

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

Mechanisms and Consequences of Drug‐Drug Interactions

The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

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