Pharmacokinetics of the Diastereoisomers of Leucovorin after Intravenous and Oral Administration to Normal Subjects1

After i.v. administration of d,l-, /-5-formyltetrahydrofolate (d,lCHO-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 concen trations greatly exceeding those of /-CHO-THF and 5-CH3-THF. The plasma half-life (ß) of the unnatural (d) isomer was 451 ±24 (S.E.) min compared to 31.6 ±1.1 min for the natural (/) isomer, and 227 ±20 min for its active metabolite, 5-CH3-THF. The halflives and volumes of distribution of each of the three compounds were independent of dose over a range of 25 to 100 mg, indicating that mechanisms for distribution, metabolism, and excretion are not saturable over the dose range tested. The urinary clearance of /-CHO-THF or 5-CH3-THF differed only slightly from creatinine clearance, whereas urinary clearance of d-CHO-THF was only one-fifth creatinine clearance, indicating that d-CHO-THF was extensively reabsorbed. Absorption of d,lCHO-THF after p.o. administration was stereoselective in that absorption of the /-isomer was approximately 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 /-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.