Effect of renal impairment on the pharmacokinetics of antimony in hamsters.

Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection with uranyl nitrate (5 mg/kg). Twenty-four h later [during acute renal failure (ARF), as indicated by the serum concentrations of creatinine and urea nitrogen] or 72 h later [during chronic renal failure (CRF)] these hamsters plus 18, uninjected, control hamsters were each given a single, intramuscular dose of sodium stibogluconate (120 mg pentavalent antimony/kg). The pharmacokinetic parameters for the antimonial drug were calculated using a non-compartmental model. Urine was collected for 72 h after similar treatment with the antimonial drug, from another 30 hamsters (10 controls, 10 with ARF, and 10 with CRF), so that the fraction of the antimony administered that was subsequently excreted in the urine could be estimated. Compared with the controls, both the hamsters with ARF and those with CRF had significantly higher maximum concentrations of antimony (C(max)), significantly larger 'areas under the curve' for the plots of blood concentration v. time, and significantly longer plasma half-lives (P < 0.001 for each). The mean (S.D.) values of C(max), for example, were more than three-fold higher in the hamsters with ARF [467.5 (59.04) microg/ml] or CRF [461.1 (68.9) microg/ml] than in the controls [154.01 (17.3) microg/ml]. The systemic clearance of antimony was also significantly lower in the hamsters with CRF than in the control animals [0.051 (0.002) v. 0.296 (0.047) litres/h/kg; P < 0.01]. In addition, the fraction of the antimony administered that was excreted in urine was significantly lower in the animals with ARF (0.25) or CRF (0.08) than in the controls (0.37), indicating significant dysfunction of the kidneys in the hamsters injected with uranyl nitrate. It seems clear that, if severe toxicity is to be avoided, patients with renal dysfunction requiring treatment (for leishmaniasis) with sodium stibogluconate should be given lower doses than similar cases with normal kidney function.

In vivo performance of parenteral theophylline-loaded polyisobutylcyanoacrylate nanoparticles in rats.

Theophylline-loaded polyisobutylcyanoacrylate (PICA) nanoparticles were prepared by emulsifier-free polymerization in aqueous media at ambient conditions. PICA nanoparticles were shown (in vitro) to be a promising controlled delivery system for theophylline. Therefore, this study was conducted to investigate the feasibility of PICA nanoparticles as a parenteral controlled drug delivery system in rats. Wistar rats were given intraperitoneal (i.p.) injections of theophylline solution (4 mg/kg) and theophylline nanospheres suspension (8 mg/kg) on two different occasions. Theophylline serum concentrations were measured by an HPLC assay. The drug solution was rapidly absorbed, distributed, and eliminated. The peak concentration (Cmax), 5.34+/-1.9 mg/l, was achieved 20 min following administration. The mean residence time was 2.94 h, and the apparent clearance was 0.31 (l/h)/kg. After nanospheres administration the mean Cmax, 2.53+/-1.1 mg/l, was attained at 3 h. The drug was successfully maintained around this elevated serum drug concentration up to 11 h in rats. The drug concentration was only reduced to 1.43+/-0.98 mg/l (i.e. reduced by 43.5%) after 20 h of administration. This present study provides evidence that the sorption of theophylline to PICA nanoparticles could control the drug release in rats.