Inhibition of Human Intestinal Wall Metabolism by Macrolide Antibiotics: Effect of Clarithromycin on Cytochrome P450 3A4/5 Activity and Expression*

Abstract

Baseline intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes.

Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N -Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults

“…Subjects were also not genotyped for CYP 3A4 and CYP 3A5. Genetic polymorphisms for CYP 3A4 and CYP 3A5 have been identified, but conflicting evidence exists regarding the functional significance of these polymorphisms (9,20,23,27,31). Based on these studies, it is inconclusive whether CYP 3A genetic polymorphisms affected our results.…”

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

“…The semi-PBPK models for clarithromycin and midazolam were developed separately using data from clinical studies and physiological parameters from the literature. The interaction models between clarithromycin and midazolam for the gut wall and liver were established from in vitro data and were subsequently validated by clinical studies (Gorski et al, 2002;Wang et al, 2004;Pinto et al, 2005). Further simulations and sensitivity analyses were performed from the validated model.…”

“…Validation Data. The clarithromycin and midazolam interaction model was validated using data from two clinical trials performed at the Indiana University School of Medicine (Gorski et al, 2002;Wang et al, 2004;Pinto et al, 2005). In both studies, healthy adult volunteers were administered 500 mg of clarithromycin orally every 12 h for 7 days.…”

“…In both studies, healthy adult volunteers were administered 500 mg of clarithromycin orally every 12 h for 7 days. In one study (n ϭ 10), upper intestinal biopsy samples were obtained before and 12 h after the last dose of clarithromycin (Pinto et al, 2005). Subjects received intravenous midazolam (2-13 mg) to achieve conscious sedation for endoscopy, and a single-point 1Ј-hydroxymidazolam/midazolam serum ratio, normalized to dose of midazolam, was used to determine hepatic CYP3A activity.…”

“…Several studies have evaluated the effect of clarithromycin on oral or intravenous midazolam disposition (Yeates et al, 1996;Gorski et al, 1998Gorski et al, , 2002Wang et al, 2004;Pinto et al, 2005). Midazolam is a commonly used in vivo probe for CYP3A activity that undergoes CYP3A-mediated hydroxylation to form 1Ј-hydroxymidazolam and 4-hydroxymidazolam (Kronbach et al, 1989;Gorski et al, 1994).…”