The pharmacokinetics of d- and l-citrovorum factor (CF) are quite different with respect to the postdistributional plasma decay rates. The natural (l) isomer had a half-life (β) of 47 ± 4 (S.E.) min compared to 143 ± 15 min for the unnatural (d) isomer. Renal clearance was the same for both isomers and was proportional to glomerular filtration rate. Urinary excretion appeared to be the only route of elimination of the d isomer, while l-CF was extensively metabolized. Consequently, the unnatural isomer accumulated in great excess over the natural isomer and its active metabolite, 5-methyltetrahydrofolate. The apparent volume of distribution was about 58% of body weight for both isomers, which indicates that they have equal access to tissue compartments. The data suggest that d-CF can compete with l-CF and 5-methyltetrahydrofolate for entry into cells. Under certain conditions, accumulation of d-CF may interfere with rescue from methotrexate toxicity.

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This work was supported by Grant CA-22866 awarded by the National Cancer Institute, Department of Health, Education and Welfare.

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