Leucovorin (Leucovorin Calcium) - Description and Clinical Pharmacology

OCTOBER 2002
1004840104

  Rx only

DESCRIPTION

Leucovorin Calcium Tablets contain either 5 mg or 25 mg leucovorin as the calcium salt of N -[4-[[(2-amino-5-formyl-1, 4, 5, 6, 7, 8-hexahydro-4-oxo-6-pteridinyl)-methyl]amino]benzoyl]- L -glutamic acid. This is equivalent to 5.40 mg or 27.01 mg of anhydrous leucovorin calcium. In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 25mg tablet also contains D&C yellow no. 10 and FD&C blue no. 1.

Leucovorin is a water soluble form of reduced folate in the folate group; it is useful as an antidote to drugs which act as folic acid antagonists. These tablets are intended for oral administration only. The structural formula of leucovorin calcium is:

C₂₀H₂₁CaN₇O₇ Molecular Weight: 511.51

CLINICAL PHARMACOLOGY

Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)- L -isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Following oral administration, leucovorin is rapidly absorbed and enters the general body pool of reduced folates. The increase in plasma and serum folate activity (determined microbiologically with Lactobacillus casei) seen after oral administration of leucovorin is predominantly due to 5-methyltetrahydrofolate.

Twenty normal men were given a single, oral 15 mg dose (7.5 mg/m²) of leucovorin calcium and serum folate concentrations were assayed with L. casei. Mean values observed (± one standard error) were:

1. Time to peak serum folate concentration: 1.72 ± 0.08 hours,
2. Peak serum folate concentration achieved: 268  ± 18 ng/mL,
3. Serum folate half-disappearance time: 3.5 hours.

Oral tablets yielded areas under serum folate concentration-time curves (AUCs) that were 12% greater than equal amounts of leucovorin given intramuscularly and equal to the same amounts given intravenously.

Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg and 37% for 100 mg.