RT Journal Article
SR Electronic
T1 Effect of methadone dose on the biliary excretion of methadone metabolites in the rat.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 407
OP 412
VO 4
IS 4
A1 D L Roerig
A1 A T Hasegawa
A1 R I Wang
YR 1976
UL http://dmd.aspetjournals.org/content/4/4/407.abstract
AB The effect of three different doses of 14C-methadone (0.08, 1.0 and 2.5 mg/kg) on the biliary excretion of methadone metabolites was studied in the rat. After administration of the 0.08- and 1.0-mg/kg doses of 14C-methadone there was no difference in the percentage of administered 14C excreted into bile with time. However, after the 2.5-mg/kg dose a significant increase was observed in the percentage of administered 14C excreted into bile. Analysis of bile samples showed that this increase was due to increases in the biliary excretion of two of the major metabolites of methadone. Several mechanisms could be responsible for this disproportionate increase in biliary excretion of methadone metabolites after high doses of methadone. It was found that the effect of high methadone dose on the biliary excretion of its metabolites was nearly eliminated when studied in phenobarbital (PB)-pretreated rats. Pretreatment of rats with PB increases the biliary excretion of methadone metabolites, primarily by increasing rates of methadone metabolism. The lack of additivity of the effect of the high dose of methadone and PB pretreatment on the biliary excretion of methadone metabolites suggests that a high dose of methadone also stimulates methadone metabolism, which results in the observed increased percentage of the administered dose excreted into bile.