Role of CYP3A4 phenotyping by midazolam clearance in predicting irinotecan pharmacokinetics.

2007 Background: Variability in the pharmacokinetics of irinotecan and its active metabolite, SN-38, is extensive and largely unexplained. Irinotecan is mainly eliminated by a cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by an esterase-cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes. Here, we prospectively explored the relationships between CYP3A phenotype and enzyme and transporter genotypes with the disposition of irinotecan. Methods: Thirty Caucasian patients with cancer were eligible, and received irinotecan as a 3-weekly 90-minute infusion (dose, 600 mg), and pharmacokinetic data were obtained using NONMEM. Four to eight days prior to the first and second cycle, patients underwent the erythromycin breath test (ERMBT; a substrate for CYP3A4 and ABCB1) and the midazolam clearance test (MCT; a substrate for CYP3A4 and CYP3A5), as putative phenotyping probes. Genomic DNA was isolated and screened for 11 known genetic variants ...