Vol. 54, Issue 4, 589-598, December 2002

Pivalate-Generating Prodrugs and Carnitine Homeostasis in Man

Eric P. Brass

Center for Clinical Pharmacology, Department of Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California

I. Introduction
II. Overview of Carnitine Homeostasis
    A. Functions of Carnitine
    B. Carnitine Balance in Humans
    C. Tissue Carnitine Content
III. Impact of Pivalate-Generating Prodrugs on Carnitine Homeostasis
    A. Metabolism of Pivalate and Cellular Impact of Pivaloylcarnitine Production
    B. Impact of Net Pivaloylcarnitine Excretion
        1. Theoretical Considerations.
        2. Animal Models.
        3. Human Studies.
        4. Considerations in Disease Populations.
IV. Regulatory Labeling of Pivalate Prodrugs
V. Conclusions and Clinical Implications
Acknowledgments
References

Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.