IMPAIRED KETOGENESIS IN CARNITINE DEPLETION CAUSED BY SHORT-TERM ADMINISTRATION OF PIVALIC ACID PRODRUG

Long-term treatment with pivalic acid prodrug results in impaired keto ne-body production. Therefore, it was of interest to investigate wheth er short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmeci llinam for 12 days to induce carnitine deficiency. The concentration o f free carnitine in serum was reduced from a mean of 42.8 mu mol/liter (range, 31-48) to 11.6 mu mol/liter (range, 7.0-24), but the muscle c arnitine concentration was not reduced. A 36-h fasting test was perfor med be fore and after drug administration to study the effect on keton e-body production. After treatment, the two subjects with the lowest l evel of serum free carnitine at the end of the fasting period had impa ired ketogenesis. This indicates a carnitine deficiency in the liver w hich was reflected in the free carnitine concentration in serum and wh ich could not be compensated for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine defi ciency and impaired fatty acid oxidation in the liver during short-ter m treatment with drugs conjugated with pivalic acid. (C) 1994 Academic Press, Inc.