Effects of verapamil on etoposide pharmacokinetics after intravenous and oral administration in rats.
Etoposide is mainly metabolized by cytochrome P450 (CYP) 3A and is a substrate for P-glycoprotein (P-gp). This study examined the effects of verapamil, a CYP3A and P-gp inhibitor, on the pharmacokinetics of etoposide in rats. A single dose of etoposide was administered via oral (p.o.; 10 mg/kg) or intravenous (i.v.; 3.3 mg/kg) routes to rats alone (control animals) or together in combination with verapamil (2 or 6 mg/kg; experimental animals). The presence of verapamil significantly increased the area under the plasma concentration-time curve (AUC); (P < 0.05; 39.2-47.6%) and significantly reduced (P < 0.01; 27.8-31.2%) the total body clearance (CLt) of p.o. administered etoposide. The absolute bioavailability (F) of etoposide increased by 1.38- to 1.47-fold. The presence of verapamil significantly increased (P < 0.01; 38.3-38.9%) the AUC and significantly reduced (P < 0.01; approximately 27%) the total body clearance (CLt) of i.v. administered etoposide. This increased bioavailability suggests that verapamil inhibits metabolic activity and elimination etoposide. The increased bioavailability of etoposide in the presence of verapamil should be taken into consideration for dosage regimens due to a potential drug interaction (DI).
Piao
Yong-Ji
YJ
College of Pharmacy, Chosun University, Kwangju, Republic of Korea.
Li
Xiuguo
X
Choi
Jun-Shik
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D005047:Etoposide; D014700:Verapamil; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A