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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Absorption kinetics of orally administered leucovorin calcium.

Oral dose proportionality and pharmacokinetics of leucovorin [(d,l)-5-formyltetrahydrofolate (5-formyl-THF)] were studied in 30 healthy male subjects. In a randomized cross-over design, 24 fasted subjects were given 4 of a series of 5 single test doses between 20 and 100 mg, at 1-week intervals, of 5-formyl-THF as an oral solution of leucovorin calcium. Six separate subjects received 200 mg iv and po in a 2-way crossover. Blood and urine samples were collected over 24 hours for differential microbiological folate assays using Lactobacillus casei and Streptococcus faecalis. Using L casei activity to measure total serum folates, the area under the concentration-time curve from 0 to infinite time (AUC[0-infinity]) was calculated. Relative bioavailabilities were 78%, 62%, 49%, and 42% for the 40-, 60-, 80-, and 100-mg doses, respectively. Both the AUC and peak concentration (CPEAK) of total folates (consisting predominantly of the major metabolite, 5-methyltetrahydrofolate (5-methyl-THF], displayed significant deviation from linearity consistent with a saturation of folate absorption. Absolute bioavailability of the 200-mg oral dose of leucovorin based on AUC was 31% compared with that of the iv dose (6,848 vs. 22,298, respectively). Total clearance, terminal half-life, and apparent volume of distribution of total folate at the 200-mg dose were not significantly different between the two routes of administration. Eighty-three percent of the biologically active iv dose was recovered in the urine within 24 hours, 31% as 5-methyl-THF. Twenty percent of the same oral dose was excreted in 24 hours, 16% as 5-methyl-THF. In contrast to the nondose-proportionality observed in total serum folates, AUC of the small component of S faecalis activity, which appeared earlier than 5-methyl-THF, displayed linear kinetics, suggestive of a distinct mechanism of uptake. As dose increased, S faecalis activity increased in relative proportion to L casei, indicating that saturation of the enzymatic bioconversion to 5-methyl-THF may also be occurring. In light of the demonstrated nondose-proportionality of total folates with oral leucovorin in this dose range, consideration should be given to parenteral administration in regimens employing higher doses. Oral administration should be at a level consistent with the capacity for efficient folate uptake.[1]


  1. Absorption kinetics of orally administered leucovorin calcium. McGuire, B.W., Sia, L.L., Haynes, J.D., Kisicki, J.C., Gutierrez, M.L., Stokstad, E.L. NCI monographs : a publication of the National Cancer Institute. (1987) [Pubmed]
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