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Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of a Novel Sorbitol Dehydrogenase Inhibitor in Healthy Participants

Landau, Zohar ; Novotny, Mark J. ; Preston, Gregory M. ; Wright, Kathryn ; Freeman, Thomas ; Dai, Haiqing ; Thompson, John ; Oates, Peter J. ; Calle, Roberto A.

Journal of Clinical Pharmacology, May 2010, Vol.50(5), pp.521-530 [Peer Reviewed Journal]

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  • Title:
    Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of a Novel Sorbitol Dehydrogenase Inhibitor in Healthy Participants
  • Author: Landau, Zohar ; Novotny, Mark J. ; Preston, Gregory M. ; Wright, Kathryn ; Freeman, Thomas ; Dai, Haiqing ; Thompson, John ; Oates, Peter J. ; Calle, Roberto A.
  • Description: 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 of 20.1 hours and t 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.
  • Is Part Of: Journal of Clinical Pharmacology, May 2010, Vol.50(5), pp.521-530
  • Identifier: ISSN: 0091-2700 ; E-ISSN: 1552-4604 ; DOI: 10.1177/0091270009336354
  • Subjects: Diabetic Complications ; Fructose ; Sorbitol ; Aldose Reductase ; Polyol Pathway

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