Pharmacokinetics of the poly-γ-glutamyl metabolites of methotrexate in skin and other tissues of rats and hairless mice

The time course of methotrexate (MTX) and its poly-γ-glutamyl metabolites (PGGs) was examined in the skin, liver and blood of rats and full-thickness skin, epidermis and blood of hairless mice to determine their contribution to the persistence of antifolate activity after a single dose of MTX. [³H]MTX was administered i.v. to rats and i.p. to mice in a dose similar, on a microgram per kilogram basis, to that administered to humans for the treatment of psoriasis. The animals were sacrificed at various times after the dose and skin and other tissues were analyzed for the presence of MTX and the PGGs. The percentage of total antifolates in the skin of rats that was attributable to the PGGs was less than 30% at all times examined (6 to 72 hr). However, more than half of the PGGs present contained three or more glutamic acid residues. The skin from the hairless mice was separated into dermis and epidermis to determine if MTX and its metabolites were present in the ostensible site of action in psoriasis, the epidermis (separation of epidermis from dermis is prohibited by hair in the rat). The PGGs accounted for less than 13% of total antifolates in full-thickness skin of mice at all times studied. The epidermis contained more antifolates, on a picomole per gram basis, at all times (4 to 24 hr) than did the full-thickness skin. In the epidermis, the percentage of total antifolates contributed by the PGGs rose to 35% by 24 hr, more than twice its value at earlier times. In both full-thickness skin and epidermis, greater than 70% of the PGGs present contained three or more glutamic acid residues. The studies indicate that although the percentage of total antifolates due to the PGGs in tissues after a low dose of MTX is small, most of the PGGs present are of the longer-chain derivatives.