Biphasic effect of methadone on hepatic drug metabolism.
When methadone HCl (30 mg/kg, po) was given acutely to mice, it was found to inhibit drug metabolism as evidenced by a prolongation of hexobarbital sleeping time and zoxazolamine paralysis time. Pharmacokinetic studies revealed that this acute dose of the narcotic analgesic could also prolong the plasma half-life of aminopyrine without any change in its volume of distribution. When added to the incubation mixture containing 10,000 g mouse liver supernatant fraction and a complete system for measuring aminopyrine N-demethylase or aniline hydroxylase, methadone showed a dose-dependent inhibition of the enzymes; the former enzyme was inhibited to a greater extent than the latter one. However, subacute treatment of mice with methadone HCl (30 mg/kg, po, twice daily for 3 days) resulted in increases in liver weight, microsomal protein, and cytochrome P-450 content in consonant with the increased activities of four hepatic drug-metabolizing enzymes: aminopyrine N-demethylase, aniline hydroxylase, p-nitroanisole, O-demethylase, and benzphetamine N-demethylase. Moreover, both hexobarbital sleeping time and zoxazolamine paralysis time were shortened. The plasma half-life of aminopyrine was decreased. These changes were prevented by simultaneous administration of puromycin diHCl (80 mg/kg, ip). Methadone thus seems to act in a manner very similar to that of propoxyphene or SKF-525A, acting as a potent inhibitor of hepatic drug metabolism when given acutely and as an inducer when given subacutely.
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006591:Hexobarbital / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013997:Time Factors; D015049:Zoxazolamine / Q000378:metabolism
D011691:Puromycin; D015049:Zoxazolamine; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D008691:Methadone