Pharmacokinetics and tissue distribution of antimony after multiple intramuscular administration in the hamster

The fate of pentavalent antimony [Sb v] in different tissues in the body after intramuscular administration is of great interest for the future study of Sb v therapy in different sitting. Pharmacokinetics and tissue distribution of antimony [Sb v] were studied in the hamster after daily dose of sodium stibogluconate equivalent to 120 mg kg -1 of Sb v, administered intramuscularly for two weeks. Liver, spleen, heart, kidney and skin tissues were isolated after blood collection at the specified time. Antimony was measured in these tissues after suitable treatment, ashing and processing, by flameless atomic absorption spectrophotometry. The concentrations of Sb v time profile in blood showed a linear rapid decline with elimination half life [t 1/2] of 1.7 h. The concentration of drug [micro g/gm] declined in a biphasic manner from almost all tissues. However, the concentrations of Sb v were declined in slower fashion from the hamster tissues than from the blood. The maximum concentration of Sb v was determined in the kidney tissues [3416 +/- 631 micro g/gm] while the lowest concentration was in the spleen [209 +/- 187 micro g/gm]. The maximum concentration of Sb v in the kidney [micro g/gm] was more than 25 fold higher than that measured from blood [micro g/ml]. The AUC of Sb v in the studied tissues was in this rank: kidney> liver> skin> spleen > heart > blood. Surprisingly, the heart, spleen and liver showed a similar t 1/2 of 5.2-6.2 h while the kidney and skin had a t 1/2 of about 3 h. Therefore, disposition of Sb v seems to kinetically follow multicompartmental model. The kidneys got the highest concentration of drug which may lead to nephrotoxicity on long term therapy

Influence of Fluvoxamine Administration on Glibenclamide Pharmacokinetics After Multiple Oral Dosing in Rats

Glibenclamide is extensively metabolized in the liver through oxidative pathways involving the cytochrome P450 system. Fluvoxamine, a potent inhibitor of cytochrome P450 [CYP] isoenzymes may be coadministered with glibenclamide. The aim of this study was to investigate whether or not fluvoxamine influences the pharmacokinetics of glibenclamide after multiple oral doses of both drugs in rats. Eighteen rats were divided into 3 groups for blood sampling. All rats received oral dose of 2.5 mg/kg for 7 days. Blood samples were collected up to 24 h after the initial dose, and on day 7 for glibenclamide. On day 8, a daily oral dose of fluvoxamine [50 mg/kg] was added and the administration of the two drugs were continued for 7 more days. On day 14, blood samples were also collected for the determination of both glibenclamide and fluvoxamine. Results indicated that following the single dose administration, glibenclamide C [max], was 415 +/- 169ng/ml, T[max], was 3.7 +/- 1.4h, t[1/2] was about 12 h and apparent clearance [C1/F] was 629 ml h[-1]kg[-1]. However, multiple dose administration of glibenclamide increased the AUC by 30% compared to the single dose. On the other hand, fluvoxamine coadministration was associated with a 16% increase in ACU. There was no significant change [p>0.05] in either C[max], or T[max]. A twenty% reduction in C1/F of glibenclamide was observed, however the difference was not significant. Therefore, the administration of fluvoxamine did not significantly alter glibenc1amide pharmacokinetic parameters. Further studies in diabetic rats or human should be performed, for a long period of time, to demonstrate if such interaction between fluvoxamine and glibenclamide is of pharmacokinetic and /or pharmacodynamic significance

Effect of experimental liver damage by CCl4 on the pharmacokinetics of zidovudine in rats

The effect of CCL4-induced hepatic damage on the pharmacokinetics of zidovudine [AZT] was investigated, in rats, in three phases. The animals were given AZT in phase I, and the results were considered as the control. In the second phase, the rats were administered an oral dose of ml/kg ccl4 to induce acute liver damage. Chronic liver damage was induced in phase III by SC injection of ccl4 [1 ml/kg] every other day for 4 weeks. Rats were administered AZT as an IP dose of 3mg/kg in the three phases. A sensitive HPLC assay was used to measure AZT serum concentrations. The mean AUC after no, acute, and chronic liver damage were 1.95,2.40, and 2.97 mg.hr/l, respectively [p<0.05]. the mean elimination half-life was significantly longer [p<0.05] in the induced chronic liver damage group [2.21 +/- 1.2 hr] compared with rats with rats with no treatment [0.7 +/- 0.23 hr] or with acute liver damage [1.31 +/- 0.28 hr]. the same trend was observed with MRT and AUMC among animals in different experiments. In addition, CI/F was significantly lower [p<0.01] for for rats in phase III compared with rats in the other phases. Rats with induced chronic liver damage eliminate AZT more slowly than rats with acute liver damage [p<0.05]. the present findings indicate that the rat model could be used tostudy the effect of liver impairment on the pharmacokinetics of AZT; the use of AZT in AIDS patients with hepatic impairmant should be closely monitored