The effects of buprenorphine on the metabolism of human hepatocytes

Adult human hepatocytes cultured in chemically defined conditions were used as a biological model to examine the metabolic effects of buprenorphine on the human liver. Cell extension and monolayer formation of human hepatocytes were affected in a dose-dependent manner after 24 hr of exposure to the drug. According to the several endpoints evaluated (cellular protein, intracellular lactate dehydrogenase activity and the MTT test), the half-maximal cytotoxic effect (IC(50)) of buprenorphine was close to 100 mum. Longer exposure of hepatocytes to buprenorphine (72 hr) increased its cytotoxicity, and the IC(50) of the drug was reduced to 50 mum. Lower concentrations of the drug (in the 5-50-mum range) significantly impaired the metabolic functions of the hepatocytes. Incubation of the cells with 40 mum-buprenorphine for 24 hr reduced the glycogen content to 60% of the initial content and 50 mum-buprenorphine inhibited glycogen synthesis in glucagon-depleted human hepatocytes by about 40%. Albumin synthesis was the most sensitive metabolic parameter, and 24-hr exposure of hepatocytes to 10 mum-buprenorphine, a concentration with no apparent cytotoxic effects, reduced albumin synthesis to 50%. Urea synthesis was moderately affected by buprenorphine. Glutathione content was reduced in a dose-dependent manner by the drug, reaching a minimum value (60% of control values) after 6 hr of exposure to 50 mum of the opiate. Analysis of the data on the therapeutic dosage of buprenorphine and other opiates showed that the toxicity risk index of buprenorphine, like that of meperidine, lies somewhere between that of morphine and methadone.