Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

Abstract

HIV infection is often associated with liver failure, which alters the pharmacokinetics of many drugs. In this study we investigated whether acute liver failure (ALF) altered the pharmacokinetics of the first-line anti-HIV agent zidovudine (AZT), a P-gp/BCRP substrate, in rats. ALF was induced in rats by injecting thioacetamide (TAA, 300 mg·kg·d, ip) for 2 days. On the second day after the last injection of TAA, the pharmacokinetics of AZT was investigated following both oral (20 mg/kg) and intravenous (10 mg/kg) administration. ALF significantly increased the plasma concentrations of AZT after both oral and intravenous doses of AZT, but without affecting the urinary excretion of AZT. AZT metabolism was studied in rat hepatic microsomes in vitro, which revealed that hepatic UGT2B7 was the main enzyme responsible for the formation of AZT O-glucuronide (GAZT); ALF markedly impaired AZT metabolism in hepatic microsomes, which was associated with the significantly decreased hepatic UGT2B7 expression. Intestinal absorption of AZT was further studied in rats via in situ single-pass intestinal perfusion. Intestinal P-gp function and intestinal integrity were assessed with rhodamine 123 and FD-70, respectively. We found that ALF significantly downregulated intestinal P-gp expression, and had a smaller effect on intestinal BCRP. Further studies showed that ALF significantly increased the intestinal absorption of both rhodamine 123 and AZT without altering intestinal integrity, thus confirming an impairment of intestinal P-gp function. In conclusion, ALF significantly increases the oral plasma exposure of AZT in rats, a result partly attributed to the impaired function and expression of hepatic UGT2B7 and intestinal P-gp.

Intestinal drug transporters in pathological states: an overview

“…Another experimental model of ALF, i.e., thioacetamide-induced liver failure, confirms observations from CCl 4 -treated rats, as significant downregulation of intestinal P-gp expression was observed. The study provided also functional confirmation of the observed changes in transporter level, since ALF significantly elevated rhodamine-123 intestinal absorption, without affecting intestinal integrity in in vivo study, which points out on deterioration of intestinal P-gp function [ 30 ].…”

“…Experimental studies in rats with thioacetamide-induced ALF revealed mild, 1.6-fold (statistically not significant) upregulation of BCRP in liver failure [ 30 ].…”

Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers

“…Metabolic, mitochondrial, renal and hepatic toxicity together with overall clinical safety issues have been attributed to antiretrovirals used for HIV management, including PIs, NRTIs and NNRTIs, due to off target interferences with physiological pathways [6,8,9,16,[39][40][41]. Entry and integrase inhibitors are supposed to be safer and free of these toxicities, however there is lack of evidence of in vivo studies [21].…”

Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

“…In vitro experiments carried out mostly in Caco-2 cells (human colon carcinoma cell line) suggest downregulation of the expression and function of ABCB1/P-gp. Exposure of the cells to plasma from animals with acute liver failure (ALF) induced by administration of carbon tetrachloride (CCl4) [51] and thioacetamide [52] proved its significantly greater inhibitory potency on P-gp-mediated rhodamine-123 transport across Caco-2 cell monolayers than plasma from control rats. Contrary to significant reduction in P-gp levels, the plasma from thioacetamide-induced ALF rats did not produce a significant impact on Caco-2 expression of BCRP [52].…”