Quantitative Correlations Among CYP3A Sensitive Substrates and Inhibitors:Literature Analysis

Ragueneau‐Majlessi, Isabelle; Boulenc, Xavier; Rauch, Clemence; Hachad, Houda; Levy, René H.

doi:10.2174/138920007782798135

Cited by 18 publications

(10 citation statements)

References 18 publications

(28 reference statements)

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“…It is known that the sensitivity of in vivo CYP probe substrates influences the magnitude of pharmacokinetic changes in the presence of perpetrators, e.g.buspirone is approximately 1.5 times more sensitive to changes in CYP3A activity than midazolam [20,21]. This arises from different pharmacokinetic properties, e.g.…”

Section: A նTwofold Change In the Clearance Of In Vivomentioning

confidence: 99%

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Polasek

Lin

Miners

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e.'perpetrate' pharmacokinetic drug-drug interactions (PK-DDIs).• Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality. WHAT THIS STUDY ADDS• This is the first study to catalogue important perpetrators of PK-DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK-DDIs.• Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK-DDIs. • Several drugs were identified which potentially perpetrate CYP-mediated PK-DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research. AIMSTo catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODSCandidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of Նsix human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (Նtwofold decrease in AUC) or weak (

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Section: A նTwofold Change In the Clearance Of In Vivomentioning

confidence: 99%

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Polasek

Lin

Miners

et al. 2011

Brit J Clinical Pharma

View full text Add to dashboard Cite

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“…The authors concluded that simvastatin was a suboptimal in vivo probe substrate because of its lack of CYP3A4 selectivity, as demonstrated by a marked increase in pharmacokinetic variability within the same patient population. However, retrospective analysis of literature in vivo DDI studies suggested that simvastatin may generally exhibit increased sensitivity to inhibition in vivo based on results from multiple CYP3A4 inhibitors (Ragueneau-Majlessi et al, 2007).…”

Section: Alternative Cyp3a4 Ddi Probe Substratesmentioning

confidence: 99%

“…However, few studies have compared the in vivo sensitivity of CYP3A4 probe substrates based on clinical DDI data from the literature (Ragueneau-Majlessi et al, 2007). Our second aim was to mine the literature for clinical CYP3A4 DDI data and correlate the in vivo DDI sensitivity of clinically relevant probe substrates with midazolam.…”

mentioning

confidence: 99%

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Foti¹,

Rock²,

Wienkers³

et al. 2010

Drug Metab Dispos

116

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ABSTRACT:Understanding the potential for cytochrome P450-mediated drugdrug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine, and testosterone. However, the design of clinical CYP3A4 DDI studies may be confounded for cases such as 1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), with which testosterone is predicted to exhibit a clinically relevant DDI whereas midazolam and felodipine/nifedipine are not. To develop an appropriate path forward for such clinical DDI studies, the inhibition potency of 20 known inhibitors of CYP3A4 were measured in vitro using 8 clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine, and sildenafil; and simvastatin, budesonide, and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil, and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil, and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, Simcyp was used to predict the in vivo magnitude of CYP3A4 DDIs caused by AMG 458 using midazolam, sildenafil, simvastatin, and testosterone as probe substrates.The cytochrome P450 (P450) superfamily of drug-metabolizing enzymes is involved in the metabolism of the majority of currently prescribed drugs and new chemical entities. Within the P450 superfamily, CYP3A4 is responsible for the metabolism of approximately 55% of marketed drugs (Wienkers and Heath, 2005). Because of its general importance in drug clearance, assessment and modeling of CYP3A4 inhibition are a critical part of the drug discovery and development process. Probe substrate-dependent inhibition profiles have been observed in vitro with CYP3A4, possibly owing to the presence of multiple probe substrate binding regions within the CYP3A4 active site (Kenworthy et al., 1999). In response, a standard approach when testing for CYP3A4 inhibition has been to use multiple probe substrates such as midazolam (the clinical standard), felodipine/nifedipine, or testosterone for in vitro experiments (Wienkers and Heath, 2005). Extrapolation of the in vitro data to the in vivo situation may be confounded in the multiple probe substrate scenario if a probe substrate that is not clinically relevant, such as testosterone, is markedly more susceptible to inhibition than midazolam (the clinical standard) and felodipine/nifedipine . Our first a...

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“…The magnitude of a DDI is dependent on the fraction metabolized (f m ) of a probe substrate for the inhibited pathway. However, to our knowledge, no studies have compared the in vivo sensitivity of CYP2C8 probe substrates on the basis of DDI data from the literature, as has been demonstrated for CYP3A4 (Ragueneau-Majlessi et al, 2007;Foti et al, 2010). Our final aim was to mine the literature for clinical DDI data and to correlate the DDI sensitivity of six probe substrates (cerivastatin, fluvastatin, montelukast, pioglitazone, repaglinide, and rosiglitazone) with known contribution to clearance from CYP2C8.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of CYP2C8 Inhibition In Vitro: Utility of Montelukast as a Selective CYP2C8 Probe Substrate

VandenBrink¹,

Foti²,

Rock³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical step in the drug discovery process. Although in vitro studies with CYP3A4, CYP2C9, and CYP2C19 have suggested the presence of multiple binding regions within the P450 active site based on probe substrate-dependent inhibition profiles, similar studies have not been performed with CYP2C8. The ability to understand CYP2C8 probe substrate sensitivity will enable appropriate in vitro and in vivo probe selection. To characterize the potential for probe substrate-dependent inhibition with CYP2C8, the inhibition potency of 22 known inhibitors of CYP2C8 were measured in vitro using four clinically relevant CYP2C8 probe substrates (montelukast, paclitaxel, repaglinide, and rosiglitazone) and amodiaquine. Repaglinide exhibited the highest sensitivity to inhibition in vitro. In vitro phenotyping indicated that montelukast is an appropriate probe for CYP2C8 inhibition studies. The in vivo sensitivities of the CYP2C8 probe substrates cerivastatin, fluvastatin, montelukast, pioglitazone, and rosiglitazone were determined in relation to repaglinide on the basis of clinical drug-drug interaction (DDI) data. Repaglinide exhibited the highest sensitivity in vivo, followed by cerivastatin, montelukast, and pioglitazone. Finally, the magnitude of in vivo CYP2C8 DDI caused by gemfibrozil-1-O-␤-glucuronide was predicted. Comparisons of the predictions with clinical data coupled with the potential liabilities of other CYP2C8 probes suggest that montelukast is an appropriate CYP2C8 probe substrate to use for the in vivo situation.

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Quantitative Correlations Among CYP3A Sensitive Substrates and Inhibitors:Literature Analysis

Cited by 18 publications

References 18 publications

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Evaluation of CYP2C8 Inhibition In Vitro: Utility of Montelukast as a Selective CYP2C8 Probe Substrate

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