In vitro identification of the cytochrome P450 isoform responsible for themetabolism of alpha-dihydroergocryptine

1. The in vitro metabolism of alpha -dihydroergocryptine (DHEC, Almirid(R)) , an ergot-derived dopamine agonist for the treatment of Parkinson's diseas e, has been studied in cultured cell lines following incubation with DHEC. Human hepatocytes as well as two sets of metabolically competent cell lines expressing one single human cytochrome P450 (1A1, 1A2, 1B1, 2A6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4) were used. 2. Mono- and dihydroxy metabolites of DHEC could only: be detected in the c ulture media of the cell line expressing human cytochrome CYP3A4. The same metabolites were found in the media of cultured human hepatocytes derived f rom three different donors. After 24-h incubation with 1 muM DHEC, similar to 60 % mono- and similar to 20 % dihydroxy metabolites were detected, i.e. similar to 80 % of DHEC was metabolized. Further, DHEC demonstrated an inh ibitory effect on CYP3A4-mediated testosterone metabolism and additionally could induce CYP3A4 and CYP2E1 mRNA when added at 10 muM to cultured human hepatocytes. 3. The data suggest that DHEC metabolism in humans is primarily mediated by the CYP3A4 isoform. The results are in accordance with findings derived fr om other ergot alkaloids.