The effect of three H₂ receptor antagonists on the disposition of cyclosporin a in the in situ perfused rat liver model

Abstract

The in situ perfused rat liver model was used to investigate the effect of three H2 receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for CyA, AM1, and the H2 receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p < 0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H2 receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H2 receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.

Effect of cimetidine on pharmacokinetics of orally administered cyclosporine in healthy dogs

“…The fact that we did not see a delay is consistent with results of other studies in which investigators have reported a lack of interaction between CyA and H 2 -receptor antagonists. 15,[17][18][19] In contrast, however, we saw a steeper slope (higher β 2 ) for the distribution phase. It is believed that a higher β 2 is unlikely to be a function of the coadministration of cimetidine, because there is not any supporting evidence in the literature that cimetidine increases the rate of elimination of CyA, and the concentration of cimetidine would have been decreasing during this time.…”

“…Noticeably, our study did not reveal significant changes in maximum concentration or the overall volume of distribution with the coadministration of cimetidine, which is consistent with other studies in which investigators reported a lack of interaction between CyA and H 2 -receptor antagonists. 15,[17][18][19] An explanation for a lack of interaction may be that cimetidine inhibits some forms of P450, whereas it does not inhibit CYP3A4, which has been identified as the specific P450 isoenzyme involved in the metabolism of CyA. 20,21 It has been documented in rats that cimetidine inhibits hepatic CYP2C, a P450 subfamily, with little or no effect on CYP3A4.…”

“…2,4 In those studies, investigators documented an interaction between CyA and ketoconazole in animals, and they suggest that cimetidine is another drug that possibly could be used to decrease metabolism of CyA and lead to higher concentrations. Although the interaction between CyA and cimetidine has been studied extensively in humans and rodents, [11][12][13][14][15][16][17][18][19] there has not been an investigation of the interaction in dogs and only sparse investigation of the pharmacokinetics of the microemulsion formulation of cyclosporine in dogs. Thus, if it could be documented that cimetidine potentiates serum concentrations of CyA, possibly through inhibition of P450 metabolism of CyA, then concurrent administration of cimetidine may decrease dose requirements of CyA in dogs.…”

Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)

“…Because biliary excretion of ranitidine and famotidine is reported as low in humans (Ͻ2.6% of dose) (Klotz and Walker, 1990), unmetabolized ranitidine and famotidine may accumulate in the liver before subsequent efflux back into blood followed by their eventual renal excretion. Studies using rat-isolated perfused liver systems seem to support the uptake and accumulation of H 2 -receptor antagonists by the liver as perfusate concentrations significantly decline over time, indicating efficient liver extraction (Mihaly et al, 1982;Hughes et al, 1995). Ranitidine and famotidine also may compete for hepatic uptake with other organic cations, potentially leading to drug-drug interactions at the level of hepatic uptake.…”