Stereoselective Metabolism of Bufuralol Racemate and Enantiomers in Human Liver Microsomes

Narimatsu, Shizuo; Takemi, Chie; Tsuzuki, Daisuke; Kataoka, Hiroyuki; Yamamoto, Satoshi; Shimada, Noriaki; Suzuki, Satoshi; Satoh, Tetsuo; Meyer, Urs; Gonzalez, Frank J.

doi:10.1124/jpet.102.036533

Cited by 17 publications

(24 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the authors found that three of the four individual samples of liver microsomes showed selectivity of formation of 1′-R-hydroxybufarolol < 1′-S-hydroxybufarolol; this was in agreement with the results from the purified recombinant CYP2D6 isozyme (Narimatsu et al, 2002). However, the fourth individual sample of liver microsome showed an opposite enantioselectivity in the formation of the metabolite (i.e.…”

Section: Screen(s) For Cyp Isozymes -Differential Activity In Vitrosupporting

confidence: 75%

“…Regardless of the mephenytoin phenotype, the carvedilol pharmacokinetics in patients was affected by the CYP2D6 phenotype only (Zhou and Wood, 1995). More recently, Narimatsu et al (2002) observed a reverse diastereoselectivity in the hydroxylation of bufarolol to 1″-hydroxy bufarolol metabolite between CYP2C19 and CYP2D6. Another recent example involving fluoxetine and norfluoxetine substrates confirmed lack of correlation between CYP2D6 and CYP2C19 genotypes when individual enantiomers were considered for the evaluation (Scordo et al, 2005).…”

Section: Lack Of Overlap Of Cyp2d6 With Cyp2c19 And/or Cyp2c9 Pathwaymentioning

confidence: 94%

“…During the study of in vitro metabolism of racemic bufarolol to its diastereomeric 1′-hydroxybufarolol metabolites, Narimatsu et al (2002) reported occurrence of differences in enantioselectivity in the conversion and was dependent on the liver microsomal samples under consideration. Interestingly, the authors found that three of the four individual samples of liver microsomes showed selectivity of formation of 1′-R-hydroxybufarolol < 1′-S-hydroxybufarolol; this was in agreement with the results from the purified recombinant CYP2D6 isozyme (Narimatsu et al, 2002).…”

Section: Screen(s) For Cyp Isozymes -Differential Activity In Vitromentioning

confidence: 98%

“…Since the enantiomers of fluoxetine are both substrates for CYP2D6 pathway and also a potent inhibitor of CYP2D6 isozyme, Fjordside et al (1999) investigated the stereoselective metabolism of fluoxetine in PMs Salva et al, 2003;McEnroe and Fleishaker, 2005Horikiri et al, 1998a,b Mautz et al, 1995Narimatsu et al, 2002Fujimaki, 1991, 1994Ducharame and Farinotti, 1996;Projean et al, 2003Yasuda et al, 2002Nomura et al, 1997Muralidharan et al, 1996Yeung et al, 1993;Hubbard et al, 1993;Chaudhary et al, 1988;Turano et al, 1972;Hollister and Curry, 1971;Sved et al, 1971;Jaworski et al, 1990Niwa et al, 2000Loh et al, 1986 Olesen andLinnet, 1999;Rochat et al, 1...…”

Section: Fluoxetinementioning

confidence: 99%

See 3 more Smart Citations

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

View full text Add to dashboard Cite

The concepts of drug development have evolved over the last few decades. Although number of novel chemical entitities belonging to varied classes have made it to the market, the process of drug development is challenging, intertwined as it is with complexities and uncertainities. The intention of this article is to provide a comprehensive review of novel chemical entities (NCEs) that are substrates to cytochrome P450 (CYP) 2D6 isozyme. Topics covered in this review aim: (1) to provide a framework of the importance of CYP2D6 isozyme in the biotransformation of NCEs as stand-alones and/or in conjunction with other CYP isozymes; (2) to provide several case studies of drug disposition of important drug substrates, (3) to cover key analytical perspectives and key assay considerations to assess the role and involvement of CYP2D6, and (4) to elaborate some important considerations from the development point of view. Additionally, wherever applicable, special emphasis is provided on chiral drug substrates in the various subsections of the review.

show abstract

Section: Screen(s) For Cyp Isozymes -Differential Activity In Vitrosupporting

confidence: 75%

Section: Lack Of Overlap Of Cyp2d6 With Cyp2c19 And/or Cyp2c9 Pathwaymentioning

confidence: 94%

Section: Screen(s) For Cyp Isozymes -Differential Activity In Vitromentioning

confidence: 98%

Section: Fluoxetinementioning

confidence: 99%

See 2 more Smart Citations

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

View full text Add to dashboard Cite

show abstract

“…It has been reported that oxidative metabolism of carvedilol is catalyzed generally by CYP2D6, which also metabolizes a number of other ␤-blockers such as metoprolol, propranolol, and bufuralol (Madani et al, 1999;Johnson et al, 2000;Narimatsu et al, 2002). However, with the exception of propranolol, there are no reports on the human UGT isoforms involved in the glucuronidation of ␤-blockers Li et al, 2001).…”

Section: Discussionmentioning

confidence: 98%

Involvement of Human Hepatic Ugt1a1, Ugt2b4, and Ugt2b7 in the Glucuronidation of Carvedilol

Ohno¹,

Saito²,

Hanioka³

et al. 2004

Drug Metab Dispos

View full text Add to dashboard Cite

This article is available online at http://dmd.aspetjournals.org ABSTRACT: Carvedilol ((؎)-1-carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol) is metabolized primarily into glucuronideconjugates. In the present study, we identified the human UDPglucuronosyltransferase (UGT) isoforms involved in the glucuronidation of carvedilol by thin-layer chromatography using microsomes from human liver or insect cells expressing recombinant UGT isoforms. We observed two forms of carvedilol glucuronides, namely G1 and G2, in hepatic microsomes. The glucuronidation of carvedilol was catalyzed by at least three recombinant UGT isoforms: UGT1A1, UGT2B4, and UGT2B7. UGT2B4 formed both G1 and G2, whereas UGT1A1 and UGT2B7 were responsible for the formation of glucuronide G2 and G1, respectively. The enzyme kinetics for carvedilol glucuronidation by UGT1A1, UGT2B4, and UGT2B7 in addition to human liver microsomes were examined by Lineweaver-Burk analysis. The values of K m and V max for human liver microsomes were 26.6 M and 106 pmol/min/mg protein for G1, and 46.0 M and 44.5 pmol/min/mg protein for G2, respectively. The K m values for UGT1A1, UGT2B4, and UGT2B7 for G1 and G2 (22.1-55.1 M) were comparable to those of the liver microsomes, whereas the V max values were in the range of 3.33 to 7.88 pmol/min/mg protein. The K m and V max /K m values for UGT2B4 and UGT2B7 for G1 were similar, whereas UGT2B4 had lower Km and higher V max /K m values for G2 compared with those of UGT1A1. These results suggest that G1 formation is catalyzed by UGT2B4 and UGT2B7, whereas G2 is formed by UGT2B4 and UGT1A1. These three hepatic UGT isoforms may have important roles in carvedilol metabolism.

show abstract

Stereoselectivity in the oxidation of bufuralol, a chiral substrate, by human cytochrome P450s

et al. 2003

Self Cite

View full text Add to dashboard Cite

Bufuralol (BF), a nonselective beta-adrenoceptor blocking agent, has a chiral center in its molecule, yielding the enantiomers 1'R-BF and 1'S-BF. beta-Adrenoceptor blocking potency is much higher in 1'S-BF than in 1'R-BF. One of the metabolic pathways of BF is 1"-hydroxylation of an ethyl group attached at the aromatic 7-position forming a carbinol metabolite (1"-hydroxybufuralol, 1"-OH-BF), and further oxidation (or dehydrogenation) produces a ketone metabolite (1-oxobufuralol, 1"-Oxo-BF). Both 1"-OH-BF and 1"-Oxo-BF are known to have beta-adrenoceptor blocking activities comparable to or higher than those of the parent drug. The 1"-hydroxylation introduces another chiral center into the BF molecule and four 1"-OH-BF diastereomers are formed from BF racemate in mammals, including humans, making elucidation of the metabolic profiles complicated. HPLC methods employing derivatization, reversed phase, or chiral columns have been developed to efficiently separate the four 1"-OH-BF diastereomers formed from BF enantiomers or racemate. Accumulated in vitro experimental results revealed that 1'R-BF is a much more preferential substrate than 1'S-BR for BF 1"-hydroxylation in human liver microsomes. Kinetic studies using recombinant human cytochrome P450 (CYP) enzymes indicate that CYP2D6 serves as a major BF 1"-hydroxylase and that CYP1A2 and CYP2C19 also contribute to BF 1"-hydroxylation in human livers. This mini-review summarizes the knowledge reported so far on the pharmacology of BF and its metabolites and the profiles of BF metabolism, especially focusing on the stereoselectivity in the oxidation of BF mainly in human livers and recombinant CYP enzymes.

show abstract

Stereoselective Metabolism of Bufuralol Racemate and Enantiomers in Human Liver Microsomes

Cited by 17 publications

References 12 publications

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Involvement of Human Hepatic Ugt1a1, Ugt2b4, and Ugt2b7 in the Glucuronidation of Carvedilol

Stereoselectivity in the oxidation of bufuralol, a chiral substrate, by human cytochrome P450s

Contact Info

Product

Resources

About