Right heart failure impairs hepatic elimination of p-nitrophenol without inducing changes in content or latency of hepatic UDP-glucuronosyltransferases.
Congestive heart failure has been shown to affect oxidative drug metabolism, however, there has been little study of its effects on drug conjugation. Using the isolated perfused livers from rats with right ventricular failure (RVF) due to pulmonary artery constriction, we studied the effects of RVF on hepatic elimination of p-nitrophenol (PNP) under controlled flow and oxygen delivery conditions. Hepatic clearance of the drug was found to be significantly impaired in RVF as compared with the sham group (0.80 +/- 0.23 versus 1.28 +/- 0.26 ml/min/g of liver). The impairment of PNP clearance in RVF occurred in parallel with significant reduction in metabolic formation clearance of p-nitrophenyl-beta-D-glucuronide; the major metabolite of PNP (0.51 +/- 0.12 versus 1.03 +/- 0.26 ml/min/g of liver). The intrinsic drug-glucuronidation capacity of livers was evaluated by measuring the microsomal content and activity of the UDP-glucuronosyltransferase(s) (UDP-GT) toward p-nitrophenol. There was no significant difference between sham and the RVF groups in either the content or the activity of the UDP-GT. The latency of the UDP-GT enzymes in microsomes was measured and was found to be similar between the two groups. The results of this study show that RVF impairs hepatic elimination of PNP and that this appears to be independent of changes in hepatic perfusion and oxygenation or alterations in hepatic content, activity, and latency of the UDP-GT.
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University of Melbourne, Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia.
Ghabrial
H
H
Morgan
D J
DJ
Ching
M S
MS
Smallwood
R A
RA
Angus
P W
PW
D000818:Animals; D004789:Enzyme Activation; D005965:Glucuronates / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009596:Nitrophenols / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018497:Ventricular Dysfunction, Right / Q000378:metabolism*
D005965:Glucuronates; D009596:Nitrophenols; C002730:4-nitrophenylglucuronide; D014453:Glucuronosyltransferase; C024836:4-nitrophenol