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Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of a Novel Sorbitol Dehydrogenase Inhibitor in Healthy Participants
Author(s) -
Landau Zohar,
Novotny Mark J.,
Preston Gregory M.,
Wright Kathryn,
Freeman Thomas,
Dai Haiqing,
Thompson John,
Oates Peter J.,
Calle Roberto A.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009336354
Subject(s) - pharmacodynamics , tolerability , pharmacology , aldose reductase , pharmacokinetics , sorbitol dehydrogenase , medicine , aldose reductase inhibitor , myalgia , adverse effect , polyol pathway , sorbitol , anesthesia , endocrinology , chemistry , diabetes mellitus , biochemistry
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.