Disposition of prothionamide in rats and armadillos.

ABSTRACT

A new method for the sensitive and selective measurement of prothionamide (PTH) and its S-oxide metabolite (PTHSO) in biological fluids was described. The limit of sensitivity was approximately 0.01 microgram of drug/ml of plasma. Endogenous materials, 2-propylisonicotinamide, ethionamide, dapsone, or monoacetyl dapsone did not interfere or contribute. Rats receiving PTH, intravenously or orally, showed a sexual dimorphism in the ability to oxidize PTH to PTHSO, with males exhibiting greater capacities for this conversion. Both sexes cleared the administered PTH more rapidly from the plasma than the metabolite, PTHSO. Following oral or intravenous administration of equimolar doses of PTHSO, both sexes exhibited an ability to reduce the administered PTHSO to PTH, with the female showing greater capacities for this conversion. Clearances after oral PTHSO administration were again more rapid for PTH than for PTHSO in both sexes. However, the total of PTH and PTHSO in the plasma during 8 hr following PTHSO administration was consistently less than following PTH dosing. Therefore, although PTHSO is retained longer than PTH after either PTH or PTHSO administration, giving PTHSO yielded less total active drug in the circulation. Comparison of plasma patterns of PTH and PTHSO in unfasted rats receiving one oral or eight daily oral doses of PTH did not indicate that PTH induces its own metabolism. Limited studies in armadillos receiving PTH and PTHSO intravenously led to the same general conclusions as those we derived from the rat studies regarding the disposition of PTH and PTHSO.