Mutual Inhibition between Carvedilol Enantiomers during Racemate Glucuronidation Mediated by Human Liver and Intestinal Microsomes

Abstract

Carvedilol is administered orally as a racemic mixture of R( )-and S( )-enantiomers for treatment of angina pectoris, hypertension and chronic heart failure. We have reported that enzyme kinetic parameters for carvedilol glucuronidation by human liver microsomes (HLM) differed greatly depending on the substrate form, namely, racemic carvedilol and each enantiomer. These phenomena were thought to be caused by mutual inhibition between carvedilol enantiomers during racemate glucuronidation. The aim of this study was to clarify the mechanism of these phenomena in HLM and human intestinal microsomes (HIM) and its relevance to uridine 5′-diphosphate (UDP)-glucuronosyl transferase (UGT) 1A1, UGT2B4 and UGT2B7, which mainly metabolize carvedilol directly in phase II enzymes. HLM apparently preferred metabolizing (S)-carvedilol to (R)-carvedilol in the racemate, but true activities of HLM for both glucuronidation were approximately equal. By determination of the inhibitory effects of (S)-carvedilol on (R)-carvedilol glucuronidation and vice versa, it was shown that (R)-carvedilol glucuronidation was more easily inhibited than was (S)-carvedilol glucuronidation. UGT2B7 was responsible for (S)-carvedilol glucuronidation in HLM. Ratios of contribution to (R)-carvedilol glucuronidation were approximately equal among UGT1A1, UGT2B4 and UGT2B7. However, enzyme kinetic parameters were different between the two lots of HLM used in this study, depending on the contribution ratio of UGT2B4, in which (R)-glucuronidation was much more easily inhibited by (S)-carvedilol than was (S)-glucuronidation by (R)-carvedilol. Meanwhile, HIM preferred metabolizing (R)-carvedilol, and this tendency was not different between the kinds of substrate form.Key words carvedilol; uridine 5′-diphosphate-glucuronosyl transferase; glucuronidation; enantiomer; interaction Many drugs are administered orally as racemic mixtures because of the difficulty or high cost of selective synthesis of one optical isomer. A pair of enantiomers has the same physicochemical properties including melting point, boiling point and solubility without optical rotation. Both enantiomers have been thought to be recognized by the same enzyme in a metabolic process because of the similarity of their chemical structures. However, these enantiomers are recognized as different chemical compounds in vivo, and pharmacological and pharmacokinetic properties often differ between enantiomers. 1)In fact, there have been several reports of interaction between enantiomers via a metabolic enzyme. 2,3)Carvedilol is an antihypertensive and antianginal drug that favorably combines β-adrenergic blocking and vasodilating activities as a result of α-blocking action. 4,5) Carvedilol is also administered orally as a racemic mixture of R(+)-and S(−)-enantiomers.It is known that carvedilol is metabolized through multiple pathways. The enzymes that are involved in its metabolism are cytochrome P450 (CYP) 2D6 and CYP2C9 as phase I enzymes and uridine 5′-diphosphate (UDP)-glucuronosyl transferase (UGT) ...

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

“…In healthy adults, glucuronidation accounts for 20-23% of total carvedilol CL (Neugebauer and Neubert, 1991) and three UGT isoforms, UGT1A1, UGT2B4, and UGT2B7, are involved in its metabolism (Ohno et al, 2004). The contributions of UGT1A1, UGT2B4, and UGT2B7 are reported to be about 30%, 25-40%, and 30-45% for R-carvedilol, and 12-20%, 15-26%, and 60-65% for S-carvedilol, respectively (Takekuma et al, 2012).…”

“…Carvedilol is a racemic mixture of two enantiomers, with S-enantiomer having both a 1 -receptor-blocking and b-adrenoreceptor-blocking activities, whereas R-enantiomer is more selective toward a 1 -receptor-blocking activity (Neugebauer et al, 1990). Both enantiomers undergo extensive stereoselective first-pass metabolism through CYP enzymes (CYP2D6, CYP1A2, CYP2C9, CYP3A4, and CYP2E1) and UGT enzymes (UGT1A1, UGT2B4, and UGT2B7) (Oldham and Clarke, 1997;Ohno et al, 2004;Takekuma et al, 2012), with reported absolute bioavailability (F) of 31.1% for R-carvedilol and 15.1% for S-carvedilol (Neugebauer et al, 1990). Because CYP2D6 is the main metabolic enzyme that is involved in the metabolism of both enantiomers and is more selective toward the overall disposition of R-carvedilol, the decrease activity of this enzyme in poor metabolizers (PMs) may result in higher systemic concentration of R-carvedilol and hence an increase in a-blockade, which can cause acute blood pressure reduction and increased incidence of orthostatic hypotension in comparison with extensive metabolizers (EMs) of CYP2D6 (Zhou and Wood, 1995).…”

<i>In Vitro</i> Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin

“…2A). Takekuma et al 16) reported that the stereoselectivity for R-and S-carvedilol glucuronidation estimated in HLM differed greatly depending on the substrate form, namely racemic carvedilol and each enantiomer. This phenomenon is thought to be caused by mutual inhibition between carvedilol enantiomers during racemate glucuronidation.…”

“…This phenomenon is thought to be caused by mutual inhibition between carvedilol enantiomers during racemate glucuronidation. 16) Therefore, to understand simply why amiodarone stimulates glucuronidation for R-carvedilol, rather than S-carvedilol, we compared the effects of amiodarone on the glucuronidation of each enantiomer separately (Fig. 2B).…”

HPLC Method Development and Validation of S(-)-Carvedilol from API and Formulations

“…Therefore the overall cardioprotective action of S(-)-Carvedilol is more and hepatotoxicity is less when compared to that of racemic and R(+)-Carvedilol [6]. In most of the cases, racemic mixtures are more preferred for oral administration than those of the enantiomer because of high cost and difficulty in selective synthesis of one optical isomer [7]. Hence there is a need to develop a validated method for the analysis of S(-)-Carvedilol from API and marketed formulations.…”