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

Foti, R.; Rock, Dan A.; Wienkers, Larry C.; Wahlstrom, Jan L.

doi:10.1124/dmd.110.032094

Cited by 117 publications

(75 citation statements)

References 24 publications

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“…Regardless of the complex mechanism of non-MichaelisMenten kinetics, ignoring it and truncating the data can lead to erroneous estimates of kinetic parameters (Lin et al, 2001). For example, TST was used in nearly 50% of reported screening studies for DDI potentials (Yuan et al, 2002), but due to its atypical kinetic, its result is difficult to extrapolate to an in vivo setting (Foti et al, 2010). Thus, it is vital to find a substrate with classic Michaelis-Menten kinetic that can serve as an ideal probe for CYP3A activity.…”

Section: Discussionmentioning

confidence: 99%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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To accurately predict the modifications done during metabolic processes by cytochrome P450 (P450) 3A enzyme, selecting substrates that best represent a broad range of substrate substitutions and that follow the Michaelis-Menten kinetic properties is highly necessary. In the present study, the oxidative pathways of deoxyschizandrin (DS), the most abundant lignan in Fructus Schisandrae fruit extract, were characterized with liver microsomes from human (HLM) and rat (RLM). Only one monohydroxylated metabolite 7(S)-hydroxylated metabolite (isoschizandrin, ISZ), was identified using liquid chromatography-mass spectrometry and nuclear magnetic resonance techniques. CYP3A4 and CYP3A5 were found to be the major isoforms involved in the monohydroxylation of DS. Also, the kinetic studies showed that DS hydroxylation obeyed MichaelisMenten kinetics both in HLM and in RLM. However, the subsequent metabolism of ISZ was nearly nonexistent when DS was present. More importantly, the interactions between DS and three well characterized CYP3A probe substrates, testosterone (TST), midazolam (MDZ), and nifedipine (NIF), were studied. TST and MDZ were shown to compete with DS for the mutual binding site, causing K m to be increased. The presence of DS also lowered the binding affinities for MDZ and TST. However, DS showed only slight inhibitory effects on nifedipine (NIF) oxidation even though NIF was able to inhibit DS hydroxylation in a noncompetitive fashion. These results show that DS is a good representative substrate of MDZ and TST primarily due to their shared, large binding regions on CYP3A. Therefore, DS is an attractive candidate as a novel CYP3A probe substrate for predicting the metabolic modifications in CYP3A activity.

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Section: Discussionmentioning

confidence: 99%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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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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“…However, a comprehensive understanding of substrate selection for CYP2D6 on the basis of in vitro and in vivo sensitivity analysis has been lacking. In addition, several P450s exhibit substrate-dependent inhibition profiles in vitro, which may confound predictions of the in vivo situation (Kenworthy et al, 1999;Stresser et al, 2000;Kumar et al, 2006;Foti and Wahlstrom, 2008;Foti et al, 2010). Predictions of CYP2D6 inhibition using quinidine, which exhibited substrate-dependent inhibition in vitro, were used to determine whether the substrate dependence translated to the in vivo situation by comparison with observed clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

VandenBrink¹,

Foti²,

Rock³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Predicting the magnitude of potential drug-drug interactions is important for underwriting patient safety in the clinical setting. Substrate-dependent inhibition of cytochrome P450 enzymes may confound extrapolation of in vitro results to the in vivo situation. However, the potential for substrate-dependent inhibition with CYP2D6 has not been well characterized. The inhibition profiles of 20 known inhibitors of CYP2D6 were characterized in vitro against four clinically relevant CYP2D6 substrates (desipramine, dextromethorphan, metoprolol, and thioridazine) and bufuralol. Dextromethorphan exhibited the highest sensitivity to in vitro inhibition, whereas metoprolol was the least sensitive. In addition, when metoprolol was the substrate, inhibitors with structurally constrained amino moieties (clozapine, debrisoquine, harmine, quinidine, and yohimbine) exhibited at least a 5-fold decrease in inhibition potency when results were compared with those for dextromethorphan. Atypical inhibition kinetics were observed for these and other inhibitor-substrate pairings. In silico docking studies suggested that interactions with Glu216 and an adjacent hydrophobic binding pocket may influence substrate sensitivity and inhibition potency for CYP2D6. The in vivo sensitivities of the clinically relevant CYP2D6 substrates desipramine, dextromethorphan, and metoprolol were determined on the basis of literature drug-drug interaction (DDI) outcomes. Similar to the in vitro results, dextromethorphan exhibited the highest sensitivity to CYP2D6 inhibition in vivo. Finally, the magnitude of in vivo CYP2D6 DDIs caused by quinidine was predicted using desipramine, dextromethorphan, and metoprolol. Comparisons of the predictions with literature results indicated that the marked decrease in inhibition potency observed for the metoprolol-quinidine interaction in vitro translated to the in vivo situation.

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

Cited by 117 publications

References 24 publications

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

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

Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

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