Plasma Stability-Dependent Circulation of Acyl Glucuronide Metabolites in Humans: How Circulating Metabolite Profiles of Muraglitazar and Peliglitazar Can Lead to Misleading Risk Assessment

Abstract

ABSTRACT:Muraglitazar and peliglitazar, two structural analogs differing by a methyl group, are dual peroxisome proliferator-activated receptor-␣/␥ activators. Both compounds were extensively metabolized in humans through acyl glucuronidation to form 1-O-␤-acyl glucuronide (AG) metabolites as the major drug-related components in bile, representing at least 15 to 16% of the dose after oral administration. Peliglitazar AG was the major circulating metabolite, whereas muraglitazar AG was a very minor circulating metabolite in humans. Peliglitazar AG circulated at lower concentrations in animal species than in humans. Both compounds had a similar glucuronidation rate in UDP-glucuronic acid-fortified human liver microsomal incubations and a similar metabolism rate in human hepatocytes. Muraglitazar AG and peliglitazar AG were chemically synthesized and found to be similarly oxidized through hydroxylation and O-demethylation in NADPH-fortified human liver microsomal incubations. Peliglitazar AG had a greater stability than muraglitazar AG in incubations in buffer, rat, or human plasma (pH 7.4). Incubations of muraglitazar AG or peliglitazar AG in plasma produced more aglycon than acyl migration products compared with incubations in the buffer. These data suggested that the difference in plasma stability, not differences in intrinsic formation, direct excretion, or further oxidation of muraglitazar AG or peliglitazar AG, contributed to the observed difference in the circulation of these AG metabolites in humans. The study demonstrated the difficulty in doing risk assessment based on metabolite exposure in plasma because the more reactive muraglitazar AG would not have triggered a threshold of concern based on the recent U.S. Food and Drug Administration guidance on Metabolites in Safety Testing, whereas the more stable peliglitazar AG would have.

Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro

“…Since DF-AG is chemically unstable, and prone to back-conversion to DF, transportermediated DDIs involving DF-AG could complicate the plasma exposure of parent DF. It is worth noting that acidification of plasma samples is a critical requirement to protect DF-AG from degradation and accurately determine the systemic exposure of DF-AG (Zhang et al, 2011). The findings in the current investigation have revealed the possibility for greater numbers of transporters involved in DF-AG disposition, and raise concerns regarding possible DDI with DF-AG.…”

Unusual Glucuronides

“…It is interesting to note that CYP2C8 has also been shown to metabolize estradiol-17␤-glucuronide to its 2-hydroxy analog (Delaforge et al, 2005). When oxidative metabolism of muraglitazar acyl glucuronide and peliglitazar acyl glucuronide was investigated in human liver microsomes fortified with NADPH, multiple oxidative metabolites of the glucuronide reference standards were observed (Zhang et al, 2011). Rates of metabolism in this study were comparable for both the acyl glucuronides.…”

Metabolism and Disposition of14C-Labeled Peliglitazar in Humans

“…This result indicated that there was very little plasma protein covalent binding, and the acyl glucuronide of peliglitazar was relatively stable in samples acidified immediately after collection and stored at Ϫ20°C. Other experiments to look at the stability of peliglitazar glucuronide were also performed, and the results are reported separately (Zhang et al, 2010).…”