Possibility of Decrease in CYP1A2 Function in Patients With End‐Stage Renal Disease

Abstract

Propranolol, the substrate of cytochrome P450 (CYP) 1A2 and CYP2D6, has been reported to be in high concentrations in end-stage renal disease (ESRD) patients. This has been thought to be due to the decrease in the nonrenal clearance of propranolol. The objective of this study is to elucidate the reason for the decrease in nonrenal clearance in ESRD patients. CYP1A2 and CYP2D6 activities were estimated by the phenacetin O-deethylation and methoprolol O-demethylation methods, respectively. Pooled normal serum and pooled uremic serum were deproteinized by methanol in order to exclude high-molecular-weight compounds. We selected as candidate inhibitors: uremic toxins such as 3-indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indole-3-acetic acid, and hippuric acid, and xanthine derivatives such as allantoin, uric acid, and xanthine. In this study, uremic serum was found to inhibit the CYP1A2-mediated metabolism of phenacetin to acetaminophen in a concentration-dependent and competitive manner. Xanthine also inhibited the metabolism of CYP1A2. On the other hand, uremic serum and the four uremic toxins did not inhibit the CYP2D6-mediated metabolism of metoprolol to O-demethylmetoprolol. In conclusion, this study suggests that the increase of the bioavailability of propranolol in ESRD is partly induced by the inhibition of the hepatic metabolism of CYP1A2 by xanthine in the uremic serum.

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

“…In experimental animal models of CKD, hepatic activity and expression levels of Cyp2d enzyme were unchanged, while those of Cyp3a family enzymes decreased. 5 Direct inhibition of CYP2D6-and CYP3A4/5-mediated microsomal metabolism was not observed after coincubation with 10% uremic serum or four uremic toxins, 22,23 while coincubation with uremic serum for 4 days decreased CYP3A4 activity in LS 180 cells (unfortunately, they did not examine the coincubation effect on CYP2D6). There are clear needs for further mechanistic studies examining elimination-route dependencies in the effect of CKD on nonrenal eliminations, and we hope that the in vivo observation in the current study will stimulate such efforts.…”

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Microbiota-derived uremic toxins also affect CYP1A activity and expression [46,55,58–60], with idole-3-acetic acid and indoxyl sulfate being the most potent. Indole-3-acetic acid decreases CYP1A2 activity by 50% in human microsomes [60].…”

“…Indole-3-acetic acid decreases CYP1A2 activity by 50% in human microsomes [60]. A combination of hippuric acid, indoxyl sulfate and p-cresol also inhibit CYP1A2 activity in human microsomes [46].…”

Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds

“…The effect of RI on such compounds is likely due to changes in DME expression, activity, protein binding, or a combination of these factors. Uremic toxins, compounds which accumulate in RI due to their decreased clearance, have been shown to alter DME expression and inhibit their activity [12,13,14,15,16]. These toxins may also affect the protein binding of drugs by competing for binding with proteins [17,18,24].…”

“…UGTs represent a major Phase II metabolic pathway, responsible for the glucuronidation of compounds [11]. It has been demonstrated that the expression and activity of these enzymes can be altered in RI, or in the presence of uremic toxins which are present at elevated levels in RI populations [12,13,14,15,16]. Furthermore, the alteration of protein binding of compounds may also alter metabolic clearance of compounds [3,17,18].…”