title: Pharmacokinetics, pharmacodynamics, tolerability, and safety of a novel sorbitol dehydrogenase inhibitor in healthy participants.
abstract: Increased glucose flux through the polyol pathway and the resultant oxidative stress is thought to be a major mechanistic contributor to microvascular diabetic complications. Inhibition of flux through this pathway can be blocked through inhibition of either of 2 enzymes, aldose reductase (AR) or sorbitol dehydrogenase (SDH). This report describes the pharmacokinetics, biomarker pharmacodynamics, and safety of CP-642,931, a potent and specific sorbitol dehydrogenase inhibitor (SDI). CP-642,931 was administered for 7 days to 57 healthy volunteers in doses ranging from 1 to 35 mg daily. After the 35-mg dose, CP-642,931 showed a t((1/2)) of 20.1 hours and t(max) at 0.5 to 1.25 hours. After a 35-mg dose, maximum inhibition of SDH was 91% (on days 1 and 7), and maximum serum sorbitol increase was 152-fold on day 7 compared to control. Five participants discontinued the study due to adverse events, including myalgia, muscle spasm, and muscle fatigue. All symptoms resolved in all but 1 participant, who continued to report intermittent muscle fasciculations upon follow-up. In conclusion, CP-642,931 is a potent and specific SDI that is rapidly absorbed through the oral route and effectively inhibits SDH. However, the drug is not well tolerated due to adverse neuromuscular effects.
authors.affiliation: Pfizer Global Research & Development, 50 Pequot Avenue, New London, CT 06320, USA.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Landau
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Novotny
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Preston
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wright
authors.forename: Thomas
authors.initials: T
authors.lastname: Freeman
authors.forename: Haiqing
authors.initials: H
authors.lastname: Dai
authors.forename: John
authors.initials: J
authors.lastname: Thompson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Calle
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D013012:Sorbitol / Q000097:blood*; D013997:Time Factors; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D013012:Sorbitol; D007064:L-Iditol 2-Dehydrogenase