KINETIC COMPARTMENTAL ANALYSIS OF CARNITINE METABOLISM IN THE HUMAN CARNITINE DEFICIENCY SYNDROMES - EVIDENCE FOR ALTERATIONS IN TISSUE CARNITINE TRANSPORT

Human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. The hypothesis that the syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle, was examined. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered i.v. to 6 normal subjects, 1 patient with primary muscle carnitine deficiency (MCD), and 4 patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 days. A 3-compartment model was adopted and rate constants, fluxes, pool sizes and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. In SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these is unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine uptake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. No radioactive metabolites of L-[methyl-3H]carnitine were found in urine, suggesting that dietary carnitine is metabolized in the gastrointestinal tract.