The change of the oxidative m etabolism of buprenorphine (BN) during repeated administration of BN was investigated in rats. The animals were pretreated intramuscularly with 4 or 8 doses of BN (0.6mg/kg) every 12hr. When BN (0.6mg/kg dose) was given intravenously to rats at 12hr after the 8 doses, it was estimated that about 95% of administered dose was recovered within 24hr as the sum of BN and norbuprenophine (NBN) conjugates in the bile. This value was not significantly different as compared with 90% in rats given intravenously at a dose of BN (0.6mg/kg) without prior intramuscular administration. However, the excretion ratio of NBN conjugate (12.8%) in the pretreated rats was significantly small as compared with 20% in the unpretreated rats (p <0.05). The pharmacokinetic profiles of NBN after intravenous administration of NBN (0.6mg/kg dose) did not change by the repeated administration of BN. The results of in vitro metabolism experiments using the tissue homogenates showed that the oxidation rate of BN in the liver pretreated with BN was decreased to one-ninth of the controls, which were given saline. These findings suggested that the decrease of the biliary excretion ratio of NBN conjugate during repeated administration of BN may be due to the decrease in metabolizing rate from BN to NBN. In exploratory studies, BN (0.003, 0.03, 0.3 and 0.6mg/kg dose) were administrated in four different doses repeatedly. The contents of cytochrome P-450 in the hepatic microsome fraction after repeated administration of 0.03, 0.3 and 0.6mg/kg doses were decreased significantly as compared with those in the control rats given saline, and were decreased 91, 84 and 71% of the contents in the pretreated rats, respectively. Both glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activities in the plasma did not change during repeated administration. These results suggested that the decrease in the metabolizing clearance from BN to NBN may be due to the decrease of cytochrome P-450 contents in the hepatic microsome.
