The sustained release of pyrimethamine base or pyrimethamine pamoate from a biodegradable injectable depot preparation in mice

Abstract

The pharmacokinetics and mass fate in mice, of pyrimethamine (425 mg kg⁻¹ s.o.) administered subcutaneously either as the base (BASE) or the pamoate salt (PAM) in an injectable oil mixture (benzyl benzoate‐peanut oil 50:50 v/v) have been evaluated. Maximum measured plasma pyrimethamine levels after BASE were attained within 24 h, and were twice as high as after PAM. 25% of animals dosed with BASE died; among the survivors plasma drug levels fell rapidly below the minimum inhibitory concentration (MIC) for Plasmodium berghei (100–200 ng ml⁻¹) by 5 weeks. In contrast, no mice dosed with PAM died and plasma levels were sustained above the MIC for 13 weeks, drug still being detectable in plasma after four months. Overall, there was no significant difference between areas under the curve from zero time to the time of the final sampling of pyrimethamine following PAM or BASE. The rapid initial elimination of ¹⁴C‐radioactivity (2ṁ64 ± 0ṁ47% dose day⁻¹ over 4 weeks) seen after dosage with [¹⁴C]BASE reflected the plasma disposition of pyrimethamine in the mice dosed with BASE. 90% of the excreted ¹⁴C was eliminated by one month by which time less than 1% (0ṁ03 ± 0ṁ02%) of the [¹⁴C]BASE was recovered from the injection site. Both BASE and [¹⁴C]BASE studies suggest that exhaustion of this preparation occurred by 7 weeks. Excretion of ¹⁴C‐radioactivity after [¹⁴C]PAM was gradual and sustained with a low mean daily rate, that was maintained throughout the study i.e. 1ṁ21 ± 0ṁ17% day⁻¹ (4 weeks), 0ṁ88 ± 0ṁ28% day⁻¹ (8 weeks), 0ṁ5 ± 0ṁ31% day⁻¹ (12 weeks), 0ṁ42 ± 0ṁ27% day⁻¹ (16 weeks). At the end of the study, 7ṁ11 ± 1ṁ90% of the [¹⁴C]PAM remained in the dose site. No visible tissue reactions were observed to either preparation. Overall recovery of radioactivity was 85ṁ00 ± 11ṁ31% for both [¹⁴C]PAM and [¹⁴C]BASE. These studies indicate that the PAM preparation is worthy of further long term evaluation.