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

Everted intestinal sacs as an in-vitro model for testing efficacy of new hypocholesterolemic agents

In the current study we investigated the effects of five new Acyl-CoA:Cholesterol acyltransferase enzyme [ACAT] inhibitors on the extent of absorption of tritiated cholesterol using the everted intestinal sacs obtained from naive or cholesterol-fed rats. The extent of absorption of cholesterol was determined in the presence of the five analogs. Everted intestinal segments from male Sprague-Dawley rats filled with serosal incubation medium were added to a mucosal solution incubation medium containing 750. [micro]M [3] H-cholesterol. The compounds were added to the mucosal solution at a concentration of 15 mM. Samples were taken from serosal fluid over a period of two hours and monitored for increases in radioactivity concentrations [[3] H-cholesterol] inside the everted sac. Comparisons were made between incubations with and without the drugs in order to assess inhibitory effects of the compounds on cholesterol absorption. All calculations were based on the extent of cholesterol accumulation at the end of two hours. Absorption of cholesterol increased considerably in the cholesterol-fed rats, relative to naive rats. This effect is thought to be due to increased ACAT enzyme activity following cholesterol pretreatment. In naive rats, the addition of the different analogs [I through V] decreased the absorption of cholesterol by 58, 49, 22, 0, and 0%, respectively. Decreases of 97, 67, 58,44 and 54% were obtained for the same compounds in cholesterol-fed rats. The parent compounds were not detected in the serosal fluids using HPLC assay, indicating poor absorption of the compounds through the intestinal wall. Significant concentrations of the drugs were detected within the intestinal tissues. The everted gut technique provided a good model for assessing the efficacy of the hypolipidemic agents based on inhibition of cholesterol absorption at a single incubation concentration

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