PHARMACOKINETICS OF THE DIASTEREOISOMERS OF LEUCOVORIN AFTER INTRAVENOUS AND ORAL-ADMINISTRATION TO NORMAL SUBJECTS

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (7) , 3114-3119
Abstract
After i.v. administration of d,l-, l-5-formyltetrahydrofolate (d,l-CHO-THF) CHO-THF was rapidly cleared from the plasma by conversion to 5-methyltetrahydrofolate (5-CH3-THF) and urinary excretion, whereas d-CHO-THF, which was not metabolized and was slowly excreted in the urine, persisted in plasma at concentrations greatly exceeding those of l-CHO-THF and 5-CH3-THF. The plasma half-life (.beta.) of the unnatural (d) isomer was 451 .+-. 24 (SE) min compared to 31.6 .+-. 1.1 min for the natural (l) isomer, and 227 .+-. 20 min for its active metabolite, 5-CH3-THF. The half-lives and volumes of distribution of each of the 3 compounds were independent of dose over a range of 25-100 mg, indicating that mechanisms for distribution, metabolism and excretion are not saturable over the dose range tested. The urinary clearance of l-CHO-THF or 5-CH3-THF differed only slightly from creatinine clearance, whereas urinary clearance of d-CHO-THF was only 1/5 creatinine clearance, indicating that d-CHO-THF was extensively reabsorbed. Absorption of d,l-CHO-THF after p.o. administration was stereoselective in that absorption of the l-isomer was .apprx. 5 times that of the d isomer. Thus, p.o. administration resulted in a more favorable ratio of active to inactive folates in plasma. At a dose of 25 mg, absorption approached 100% for l-CHO-THF compared to 20% for d-CHO-THF. However, absorption was saturable, and lower percentages of both compounds were absorbed at doses of 50 and 100 mg. [Leucovorin calcium, the soluble calcium salt of CHO-THF, is used to treat or prevent host toxicity due to the antineoplastic drug methotrexate.].