The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs.
Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.
Kukanich
B
B
Department of Molecular Biomedical Sciences, Comparative Pain and Pharmacology Research Laboratory, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA. kukanich@ksu.edu
Lascelles
B D X
BD
Aman
A M
AM
Mealey
K L
KL
Papich
M G
MG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D007275:Injections, Intravenous / Q000662:veterinary; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D054328:Proton Pump Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D007654:Ketoconazole; D008691:Methadone