title: The biotransformation of the ergot derivative CQA 206-291 in human, dog, and rat liver slice cultures and prediction of in vivo plasma clearance.
abstract: Liver slice cultures from 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 Vmax/Km of human and rat liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Drug Safety Assessment, Sandoz Pharma Ltd, Basel, Switzerland.
authors.forename: A E
authors.initials: AE
authors.lastname: Vickers
authors.forename: S
authors.initials: S
authors.lastname: Connors
authors.forename: M
authors.initials: M
authors.lastname: Zollinger
authors.forename: W A
authors.initials: WA
authors.lastname: Biggi
authors.forename: A
authors.initials: A
authors.lastname: Larrauri
authors.forename: J P
authors.initials: JP
authors.lastname: Vogelaar
authors.forename: K
authors.initials: K
authors.lastname: Brendel
mesh_terms: D000328:Adult; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015259:Dopamine Agents / Q000097:blood / Q000493:pharmacokinetics*; D004873:Ergolines / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015259:Dopamine Agents; D004873:Ergolines; C059483:CQA 206-291