The disposition of pyrimethamine base and pyrimethamine pamoate in the mouse: Effect of route of administration

✍ Scribed by M. D. Coleman; G. W. Mihaly; G. Edwards; R. E. Howells; A. M. Breckenridge

• Publisher: John Wiley and Sons
• Year: 1986
• Tongue: English
• Weight: 495 KB
• Volume: 7
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510070208

✦ Synopsis

We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutanous (s.c.) routes. Following the administration of pyrimethamine base (i .p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially . There was no significant difference between these three groups in the clearance (0.29 k 0.05, 0.30 f 0.03, 0.26 k 0.05ml min-'), elimination half-life (4.5 f 0.5,44 k 0.8, 4.9 f 0.5 h) and AUC (19.4 f 4.4, 17.3 k 2.2, 21.1 k 4.4bg.hml-').

By contrast, after S.C. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups.

The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of I4C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for.

These studies indicate that of the four treatment groups only pyrimethamine pamoate on S.C. administration demonstrates a sustained release action from the dose site. This effect is not accompanied by any differences in AUC, clearance, and rate of elimination, when compared with the base given i.p. and s.c., or the pamoate salt given i.p., the latter groups displaying no slow release characteristics.