The biotransformation of the ergot derivative CQA 206-291 in human, dog, and rat liver slice cultures and prediction of in vivo plasma clearance
Vickers, A.E.; Connors, S.; Zollinger, M.; Biggi, W.A.; Larrauri, A.; Vogelaar, J.P.; Brendel, K.
Drug Metabolism and Disposition the Biological Fate of Chemicals 21(3): 454-459
1993
ISSN/ISBN: 0090-9556 PMID: 8100501 Document Number: 413590
Liver slice cultures for humans, dogs, and rats were used to investigate the biotransformation of the dopaminergic ergot agonist CQA 206-291 and to predict pharmacokinetic values for hepatic intrinsic clearance and plasma clearance. CQA 206-291 was extensively metabolized in the liver slice cultures and in vivo. The HPLC metabolite patterns from the liver slice cultures were similar for all three species, indicating the occurrence of the same metabolic pathways for CQA 206-291 biotransformation. The rate of formation of CQ 32-084, a pharmacologically active N-deethylated metabolite, exceeded that of metabolite d, a primary metabolite, by 1.4 fold in human liver slices, and by 1.7 fold in rat liver slices. In dog liver slice cultures, metabolite d formation exceeded CQ 32-084 formation by 1.3 fold and was formed at a statistically significantly greater rate (3 fold) than in either human or rat liver slices. The metabolism of ergots like CQA 206-291 by human fetal liver was also demonstrated in this study. However, the prominent metabolite from fetal and adult human liver microsomes was metabolite d with minor amounts of CQ 32-089 being formed. A major route of excretion for the metabolites of CQA 206-291 is the kidney, yet the kidney does not contribute to the metabolism of CQA 206-291. Kidney slices derived from humans, rats, and dogs did not metabolize CQA 206-291 within 24 hr. CQA 206-291 intrinsic clearance was derived from the half-life of parent drug disappearance in the liver slice and hepatocyte cultures, and from the ratio of V-max/K-M of human and rat liver microsomes. A prediction of CQA 206-291 plasma clearance (CL) was calculated from the equation of a well-stirred model. The predicted CL values from slices were lower than the in vivo values by 8 fold for humans, 5 fold for dogs, and 3.5 fold for rats; however, the species ranking was the same with the CL greatest for rats (0.96 liters/hr/kg), followed by dogs (0.32 liters/hr/kg) and then humans (0.15 liters/hr/kg). Hepatocytes yielded an equivalent prediction as the slices. The CL predictions from liver microsomes were closer to the in vivo values, particularly for humans indicating that the access of CQA 206-291 to the cytochrome P-450 enzymes was slower in the slices and hepatocytes. In summary, the in vitro data predicted that CQA 206-291 was a high hepatic extraction drug with a high first-pass effect, which was supported by the in vivo findings demonstrating a high first-pass and low bioavailability. The slice cultures are predictive of biotransformation pathways and pharmacokinetic parameters of CQA 206-291 and probably other ergot derivatives, thereby allowing for the comparison of species and ranking of compounds.