title: Pharmacokinetics and tissue distribution of the renin inhibitor N-(2-(R)-benzyl-3-tert-butyl-sulfonyl-propionyl)-His-ChacVal-n-butylami ne in marmosets.
abstract: The fate of CGP 38 560 [N-(2-(R)-benzyl-3-tert-butyl-sulfonyl-propionyl)-His-ChacVal-n-bu tylamine], a potent renin inhibitor, has been studied in marmosets. [3H]CGP 38 560 is rapidly cleared from the plasma. The elimination process is biphasic, with a t1/2 of 4.8 +/- 1.0 min (mean +/- SD) in the first phase and 26.6 +/- 8.4 min (mean +/- SD) in the second. The kinetics of elimination from plasma are similar when measured both in a radio-inhibitor binding assay and radiometrically using 3H-labeled substance. The drug is mainly eliminated in the bile, almost 73.8% of the i.v. administered dose being excreted within the first 60 min. It is detectable in bile in both unchanged (8.6%) and metabolized form. HPLC analysis of bile extracts showed at least five tritiated peaks representing constituents capable of binding human renin (A, B, C, D, and E). These fractions were isolated, purified, and analyzed by mass spectrometry. Peak E corresponded to unchanged CGP 38 560. Metabolites A, B, C, and D are more polar than the parent compound, as indicated by their retention times upon HPLC analysis. The metabolic pathways inferable from the respective molecular weights are hydroxylation, oxygenation, and, in one case, cleavage of the n-butylamino group located at the COOH-terminal. From comparisons of the pharmacokinetic parameters after iv (0.1 mg/kg) and oral (10 mg/kg) administration, it can be estimated that the bioavailability of CGP 38 560 in the marmoset is 0.3%.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Cumin
authors.forename: C
authors.initials: C
authors.lastname: Schnell
authors.forename: P
authors.initials: P
authors.lastname: Richert
authors.forename: F
authors.initials: F
authors.lastname: Raschdorf
authors.forename: A
authors.initials: A
authors.lastname: Probst
authors.forename: K
authors.initials: K
authors.lastname: Schmid
authors.forename: J M
authors.initials: JM
authors.lastname: Wood
authors.forename: M
authors.initials: M
authors.lastname: de Gasparo
mesh_terms: D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D002143:Callitrichinae; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D009842:Oligopeptides / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D000092502:Renin Inhibitors
chemical_list: D009842:Oligopeptides; D000092502:Renin Inhibitors; C060150:CGP 38560