title: Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme, in the rat.
abstract: 1. The route of elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme (ACE), has been investigated in the anaesthetized rat. Comparisons have been made with other ACE inhibitors. 2. Bile and urine samples were collected over a 5 hour period following a single i.v. dose of ACE inhibitor (2 mumol kg-1). Samples were bioassayed for ACE inhibitory activity using affinity-purified rabbit lung ACE and the amounts of the active form of inhibitor present in each sample were calculated by comparison with a standard curve. 3. FPL 63547 was rapidly and extensively excreted as the diacid in the bile but appeared in the urine in negligible amounts. The bile:urine ratio was 21.4:1 indicating a marked preference for the biliary route. A similar elimination profile was observed when the compound was dosed in its active form (FPL 63547 diacid), 87.9% of which was found in the bile over the 5 h collection period, with a bile: urine ratio of 14.6:1. 4. The marked preference of FPL 63547 for biliary elimination was not shared by the other ACE inhibitors tested in this study. Lisinopril demonstrated the opposite pattern, being excreted almost exclusively by the kidney (bile:urine ratio 0.06:1). Enalapril was eliminated in approximately equal amounts in bile and urine (ratio 0.7:1) while spirapril diacid showed a slight preference for the bile (ratio 2.6:1). 5. The physical chemical properties of FPL 63547 diacid may be responsible for its unusual preference for biliary elimination. In particular, the amphipathic character and strong acid functionality of the compound are thought to favour transport into the bile. 6. Elimination by the biliary route will be preferred in patients whose renal function is impaired as a result of disease or age. In such patients the elimination of renally-excreted ACE inhibitors is known to be compromised, resulting in compound accumulation and the need for closer monitoring. Therefore, the elimination profile of FPL 63547, if confirmed in man, may prove to be clinically advantageous.
authors.affiliation: Department of Pharmacology, Fisons plc, Research and Development Laboratories, Loughborough, Leics.
authors.forename: R D
authors.initials: RD
authors.lastname: Carr
authors.forename: A E
authors.initials: AE
authors.lastname: Cooper
authors.forename: R
authors.initials: R
authors.lastname: Hutchinson
authors.forename: J
authors.initials: J
authors.lastname: Mann
authors.forename: S E
authors.initials: SE
authors.lastname: O'Connor
authors.forename: D H
authors.initials: DH
authors.lastname: Robinson
authors.forename: E
authors.initials: E
authors.lastname: Wells
mesh_terms: D000758:Anesthesia; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D004656:Enalapril / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D017706:Lisinopril; D008168:Lung / Q000201:enzymology; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013830:Thiadiazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D013830:Thiadiazoles; D004656:Enalapril; C065021:utibapril; D017706:Lisinopril