Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam

• Published in: Xenobiotica Vol. 49; no. 12; pp. 1470 - 1477
• Main Authors: Fukuno, Shuhei, Nagai, Katsuhito, Fujiike, Mai, Sasaki, Yuya, Konishi, Hiroki
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.12.2019
• Subjects: 5-fluorouracil; Administration, Intravenous; Animals; Body Weight - drug effects; CYP3A; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Fluorouracil - pharmacokinetics; Hydroxylation - drug effects; Inactivation, Metabolic; Kinetics; Liver - drug effects; Liver - metabolism; Male; metabolic elimination; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; midazolam; Midazolam - administration & dosage; Midazolam - blood; Midazolam - pharmacokinetics; Organ Size - drug effects; pharmacokinetics; Rats, Sprague-Dawley; 5-fluorouracil; pharmacokinetics; CYP3A; metabolic elimination; midazolam
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2019.1578004

1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1′-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CL tot ) and elimination rate constant (k e ) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes. 4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.