title: The physiological disposition of lovastatin.
abstract: Lovastatin is a pro-drug lactone whose open chain beta-hydroxy-acid (HA) is a potent inhibitor of hydroxymethylglutaryl-CoA-reductase and thus of cholesterol synthesis. Because the liver is the major site of cholesterolgenesis, it is the principal target organ for agents of this class. In animals, lovastatin is not as well absorbed as HA given per se, but that fraction that is absorbed reaches the portal circulation largely unchanged and is more efficiently extracted by the liver, after which it is reversibly biotransformed to HA and irreversibly to other enzymatically active products. These, like HA, maintain high hepatic gradients relative to all tissues examined. The minimal systemic burden for HA is attributable in part to the metabolic equilibrium, lovastatin in equilibrium HA, the opposing reactions for which appear to be present in most tissues. Excretion is very largely biliary in all species. Detailed comparisons of absorption, distribution, metabolism, and excretion profiles presented here and elsewhere indicate dogs to be the most appropriate paradigm for humans for study of lovastatin disposition.
authors.affiliation: Merck Institute for Therapeutic Research, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: D E
authors.initials: DE
authors.lastname: Duggan
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: W F
authors.initials: WF
authors.lastname: Bayne
authors.forename: R A
authors.initials: RA
authors.lastname: Halpin
authors.forename: C A
authors.initials: CA
authors.lastname: Duncan
authors.forename: M S
authors.initials: MS
authors.lastname: Schwartz
authors.forename: R J
authors.initials: RJ
authors.lastname: Stubbs
authors.forename: S
authors.initials: S
authors.lastname: Vickers
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D004285:Dogs; D005243:Feces / Q000032:analysis; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000097:blood / Q000493:pharmacokinetics*; D008251:Macaca; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D008148:Lovastatin