Physiologically Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin

• DOI: 10.1124/dmd.109.028746
• Publication Date: 2009-11-03T02:54:56Z
• Authors: Sara K. Quinney; Xin Zhang; Aroonrut Lucksiri; J. Christopher Go...; Lang Li; Stephen D. Hall
• Keywords: CYP3A; Midazolam

The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors CYP3A is complicated when the inhibitor itself metabolized by CYP3Aas in case clarithromycin. Previous attempts predict effects clarithromycin on substrates, e.g., midazolam, failed account for nonlinear metabolism A semiphysiologically based pharmacokinetic model was developed and midazolam metabolism, incorporating hepatic intestinal non-CYP3A mechanisms. inactivation occurred at both sites. <i>K</i>_I <i>k</i>_inact values obtained from vitro sources were unable accurately effect activity. An iterative approach determined optimum vivo be 5.3 μM <i>K</i>_i 0.4 4 h⁻¹ liver intestines, respectively. incorporation CYP3A-dependent enabled its pharmacokinetics. predicted 2.6-fold change intravenous area under plasma concentration-time curve (AUC) after 500 mg orally twice daily consistent with observations. Although mean 5.3-fold AUC oral lower than observed values, it within range Intestinal activity less sensitive changes <i>K</i>_I, <i>k</i>_inact, half-life CYP3A. This intestine predicts pharmacokinetics DDI between midazolam. Furthermore, this framework can applied other inhibitors.