THE BIOTRANSFORMATION OF THE ERGOT DERIVATIVE CQA 206-291 IN HUMAN, DOG, AND RAT-LIVER SLICE CULTURES AND PREDICTION OF INVIVO PLASMA-CLEARANCE

Liver slice cultures from humans, dogs, and rats were used to investig ate the biotransformation of the dopaminergic ergot agonist CQA 206-29 1 and to predict pharmacokinetic values for hepatic intrinsic clearanc e and plasma clearance. CQA 206-291 was extensively metabolized in the liver slice cultures and in vivo. The HPLC metabolite patterns from t he liver slice cultures were similar for all three species, indicating the occurrence of the same metabolic pathways for CQA 206-291 biotran sformation. The rate of formation of CQ 32-084, a pharmacologically ac tive N-deethylated metabolite, exceeded that of metabolite d, a primar y metabolite, by 1.4 fold in human liver slices, and by 1.7 fold in ra t liver slices. In dog liver slice cultures, metabolite d formation ex ceeded CQ 32-084 formation by 1.3 fold and was formed at a statistical ly significantly greater rate (3 fold) than in either human or rat liv er slices. The metabolism of ergots like CQA 206-291 by human fetal li ver was also demonstrated in this study. However, the prominent metabo lite from fetal and adult human liver microsomes was metabolite d with minor amounts of CO 32-089 being formed. A major route of excretion f or the metabolites of CQA 206-291 is the kidney, yet the kidney does n ot contribute to the metabolism of CQA 206-291. Kidney slices derived from humans, rats, and dogs did not metabolize CQA 206-291 within 24 h r. CQA 206-291 intrinsic clearance was derived from the half-life of p arent drug disappearance in the liver slice and hepatocyte cultures, a nd 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 th e equation of a well-stirred model. The predicted CL values from slice s 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 yi elded an equivalent prediction as the slices. The CL predictions from liver microsomes were closer to the in vivo values, particularly for h umans indicating that the access of CQA 206-291 to the cytochrome P-45 0 enzymes was slower in the slices and hepatocytes. In summary, the in vitro data predicted that CQA 206-291 was a high hepatic extraction d rug 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 pharma cokinetic parameters of CQA 206-291 and probably other ergot derivativ es, thereby allowing for the comparison of species and ranking of comp ounds.