Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects.
After i.v. administration of d,l-, 1-5-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 (S.E.) 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 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 l-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,l-CHO-THF after p.o. administration was stereoselective in that absorption of the l-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 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.
D000284:Administration, Oral; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000502:physiology; D007700:Kinetics; D002955:Leucovorin / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002955:Leucovorin