COMBINATION OF REDUCED FOLATES WITH METHOTREXATE OR 5-FLUOROURACIL - COMPARISON BETWEEN 5-FORMYLTETRAHYDROFOLATE (FOLINIC ACID) AND 5-METHYLTETRAHYDROFOLATE IN-VITRO ACTIVITIES

Folinic acid (dl FA) is increasingly used in clinical oncology. The ac tive isomer l FA is intensively metabolized into l 5-methyltetrahydrof olate (l 5MTHF), the relative proportions of l FA, d FA and l 5MTHF in blood varying considerably between oral and i.v. FA administration. T he purpose of the study was to compare the in vitro activities of pure l FA and pure l 5MTHF at equivalent drug exposure [area under curve ( AUC)], taking into account their respective chemical stability in the culture medium. The in vitro growth inhibition [3-(4,5-dimethylthiazol -2-yl)-2,5 diphenyltetrazolium bromide (MTT) test] was evaluated on fi ve human tumor cell lines after methotrexate (MTX)-folate or 5-fluorou racil (5FU)-folate exposures. Not only were the activities of l FA and l 5MTHF compared, but also clinically relevant mixtures of l FA + d F A + l 5MTHF corresponding to the proportions found at steady state dur ing oral (PO mixture, 4, 39 and 57%, respectively) and i.v. administra tions (i.v. mixture, 7, 81 and 12%, respectively). Measurement of fola tes demonstrated the marked lability of 15MTHF (65.8% loss over 5 days in the culture medium) as compared to l FA (2.6% loss). Whatever the pharmacological model tested (MTX-folate or 5FU-folate), comparison of the folate effects at equivalent drug exposure taking into account th eir relative stability showed that l 5MTHF was never more potent than l FA. Moreover, a higher efficiency of I FA was demonstrated for the c ell line most sensitive to 5FU; in this case, as expected, the i.v. mi xture was more potent than the PO mixture. This study shows that depen ding on the tumor, l FA can be more potent than its main circulating m etabolite l 5MTHF. Along with the limited capacity of oral absorption, the choice between oral and i.v. route for FA administration in patie nts should take into consideration the different pharmacological activ ities between l FA and l 5MTHF which suggest that the oral route is po tentially detrimental to the optimal activity of the 5FU-FA combinatio n as compared to i.v. administration.