PIII-62Metabolism of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, by human cytochrome P-450 CYP3A4, 3A5, 1A1, and 1A2

Abstract

BACKGROUND Erlotinib (E), an EGFR inhibitor, is approved for the treatment of non-small cell lung cancer. E is extensively metabolized and exhibits wide inter-subject pharmacokinetic (PK) variability. The objective was to characterize E metabolism by human CYP enzymes. METHODS E (1.5–50 μM) was incubated with recombinant human CYP3A4, 3A5, 3A7, 1A1, 1A2, and 1B1 (10–160 pmol/ml) at 370C for 30 min. E and metabolites were monitored by HPLC with PDA detector. Enzyme kinetics was examined by fitting substrate concentration-reaction velocity curve to Hill equation or Michealis-Menten function using WinNonlin. RESULTS E was metabolized primarily by CYP3A4, 3A5, and 1A1, to a lesser extent by 1A2, and to a negligible extent by 3A7 and 1B1. Values for maximum clearance (CLmax), representing overall E metabolism, were 0.24, 0.21, 0.31, and 0.15 ml/min/nmol P450 for reactions with CYP3A4, 3A5, 1A1, and 1A2, respectively. The formation kinetics of OSI-420, a main and active in vivo metabolite of E, were characterized by assessment of intrinsic clearance (CLint); values were 0.09, 0.05, 0.02, and 0.03 ml/min/nmol P450 for reactions with CYP3A4, 3A5, 1A1, and 1A2, respectively. CONCLUSIONS In addition to CYP3A4, 3A5 and 1A1 have significant metabolic capability for overall E metabolism. In smokers, induction of hepatic and/or intratumoral CYP1A1 may represent a predominant elimination pathway for E. Polymorphisms in CYP3A4/5 and CYP1A1 and smoking status may contribute to E PK variability and treatment outcome. Clinical Pharmacology & Therapeutics (2005) 79, P75–P75; doi: 10.1016/j.clpt.2005.12.270