Pharmacokinetics, pharmacodynamics, tolerability, and safety of a novel sorbitol dehydrogenase inhibitor in healthy participants.
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.
Landau
Zohar
Z
Pfizer Global Research & Development, 50 Pequot Avenue, New London, CT 06320, USA.
Novotny
Mark J
MJ
Preston
Gregory M
GM
Wright
Kathryn
K
Freeman
Thomas
T
Dai
Haiqing
H
Thompson
John
J
Oates
Peter J
PJ
Calle
Roberto A
RA
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
D004791:Enzyme Inhibitors; D013012:Sorbitol; D007064:L-Iditol 2-Dehydrogenase