Influence of protein binding on the metabolic clearance rate of synthetic progestins in the rat liver perfusion model.
Levonorgestrel (LN), 3-Keto-desogestrel (KDG), norethisterone (NET), and gestodene (GST) were investigated in the recirculating rat liver perfusion model. Progestins were dissolved in buffered salt solution (MI), BSA containing (MII) or HSA and sex hormone binding globulin (SHBG) containing medium (MIII) at a concentration of about 60 ng/ml. Each 3-5 female rat livers were perfused with MI, MII, and MIII for 1 h. Perfusion medium, liver biopsies and total bile were analyzed for progestin levels by specific radioimmunoassays. Protein binding characteristics were determined in media and tissue. In all experiments bile (remaining liver) contained less than 1% (3%) of respective progestin dose demonstrating an almost complete biotransformation of all drugs by rat livers, irrespective of used medium. With MI, metabolic clearance rates (MCRs) and half-lives (t1/2) were not different for the four progestins. With MII, the actual progestin levels were generally higher than with MI, but half-lives were not changed. MCRs were close to the perfusion rate at the start of experiments but decreased to about 50%. MCRs of free and total drug levels were identical. Protein binding of 70-80% did not change with time. With MIII, the half-lives increased 1.5 fold (NET), 2.8 fold (KDG), 3.1 fold (GST) and 3.2 fold (LN) and MCRs accounted for 50-70% of perfusion rate at the beginning. The time courses of further MCR decreases were different for the various progestins and can be attributed to differences in specific binding of drugs to SHBG. Clearly, the presence of SHBG in MIII induced a shift of drug from liver tissue into the perfusion medium.(ABSTRACT TRUNCATED AT 250 WORDS)
Zuo
M
M
Institute of Pharmacokinetics, Schering Aktiengesellschaft, Berlin/Bergkamen, Fed. Rep. of Germany.
Karras
D
D
Hümpel
M
M
D000818:Animals; D001646:Bile / Q000378:metabolism; D005260:Female; D006207:Half-Life; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D009929:Organ Size; D010477:Perfusion; D011372:Progestins / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism
D011372:Progestins; D012709:Serum Albumin; D012738:Sex Hormone-Binding Globulin