Impact of the simultaneous administration of the (+)- and (-)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (-)-tetrahydrofolic acid.
OBJECTIVE
To detect possible interactions between (-)-formyl-tetrahydrofolic acid (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration.


METHODS
Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (-)-fTHF and (+/-)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of (14)C-(-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure.


RESULTS
The pharmacokinetic parameters obtained for (-)-fTHF following the administration of (-)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 microg. h/ml; maximum concentration, 12 microg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (+/-)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (-)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of (14)C-(-)-mTHF did not depend on the presence of (+)-mTHF at either concentration.


CONCLUSIONS
These data suggest that (-)-fTHF is not therapeutically superior to (+/-)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.
Schleyer
E
E
Carl-Gustav-Carus-University, Department of Internal Medicine I, Dresden, Germany.
Rudolph
K L
KL
Braess
J
J
Unterhalt
M
M
Ehninger
G
G
Hiddemann
W
W
Kern
W
W
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D002955:Leucovorin / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil