Full Text:   <1542>

CLC number: R96

On-line Access: 

Received: 2007-03-02

Revision Accepted: 2007-09-04

Crosschecked: 0000-00-00

Cited: 0

Clicked: 2861

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2007 Vol.8 No.10 P.756~764

10.1631/jzus.2007.B0756


Stereoselective glucuronidation of carvedilol by Chinese liver microsomes


Author(s):  YOU Lin-ya, YU Chun-na, XIE Sheng-gu, CHEN Shu-qing, ZENG Su

Affiliation(s):  Department of Drug Metabolism and Pharmaceutical Analysis, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

Corresponding email(s):   zengsu@zju.edu.cn

Key Words:  Carvedilol (CARV), Derivatization, Stereoselectivity, Enzyme kinetics, Chinese liver microsomes


YOU Lin-ya, YU Chun-na, XIE Sheng-gu, CHEN Shu-qing, ZENG Su. Stereoselective glucuronidation of carvedilol by Chinese liver microsomes[J]. Journal of Zhejiang University Science B, 2007, 8(10): 756~764.

@article{title="Stereoselective glucuronidation of carvedilol by Chinese liver microsomes",
author="YOU Lin-ya, YU Chun-na, XIE Sheng-gu, CHEN Shu-qing, ZENG Su",
journal="Journal of Zhejiang University Science B",
volume="8",
number="10",
pages="756~764",
year="2007",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.2007.B0756"
}

%0 Journal Article
%T Stereoselective glucuronidation of carvedilol by Chinese liver microsomes
%A YOU Lin-ya
%A YU Chun-na
%A XIE Sheng-gu
%A CHEN Shu-qing
%A ZENG Su
%J Journal of Zhejiang University SCIENCE B
%V 8
%N 10
%P 756~764
%@ 1673-1581
%D 2007
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.2007.B0756

TY - JOUR
T1 - Stereoselective glucuronidation of carvedilol by Chinese liver microsomes
A1 - YOU Lin-ya
A1 - YU Chun-na
A1 - XIE Sheng-gu
A1 - CHEN Shu-qing
A1 - ZENG Su
J0 - Journal of Zhejiang University Science B
VL - 8
IS - 10
SP - 756
EP - 764
%@ 1673-1581
Y1 - 2007
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.2007.B0756


Abstract: 
Objective: To study the stereoselective glucuronidation of carvedilol (CARV) by three chinese liver microsomes. Methods: The metabolites of CARV were identified by a hydrolysis reaction with β-glucuronidase and HPLC-MS/MS. The enzyme kinetics for CARV enantiomers glucuronidation was determined by a reversed phase-high pressure liquid chromatography (RP-HPLC) assay using (S)-propafenone as internal standard after precolumn derivatization with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylisothiocyanate. Results: Two CARV glucuronides were found in three chinese liver microsomes incubated with CARV. The non-linear regression analysis showed that the values of Km and Vmax for (S)-CARV and (R)-CARV enantiomers were (118±44) µmol/L, (2 500±833) pmol/(min·mg protein) and (24±7) µmol/L, (953±399) pmol/(min·mg protein), respectively. Conclusion: These results suggested that there was a significant (P<0.05) stereoselective glucuronidation of CARV enantiomers in three chinese liver microsomes, which might partly explain the enantioselective pharmacokinetics of CARV.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1] Eggertsen, R., Sivertsson, R., Andren, L., Hansson, L., 1987. Acute and long-term hemodynamic effects of carvedilol, a combined beta-adrenoceptor blocking and precapillary vasodilating agent, in hypertensive patients. J. Cardiovasc. Pharmacol., 10(Suppl. 11):97-100.

[2] Fujimaki, M., 1994. Oxidation of R(+)- and S(−)-carvedilol by rat liver microsomes. Evidence for stereoselective oxidation and characterization of the cytochrome P450 isozymes involved. Drug Metab. Dispos., 22(5):700-708.

[3] Fujimaki, M., Murakoshi, Y., Hakusui, H., 1990. Assay and disposition of carvedilol enantiomers in humans and monkeys: evidence of stereoselective presystemic metabolism. J. Pharm. Sci., 79(7):568-572.

[4] Fujimaki, M., Shintani, S., Hakusui, H., 1991. Stereoselective metabolism of carvedilol in the rat. Use of enantiomerically radiolabeled pseudoracemates. Drug Metab. Dispos., 19(4):749-753.

[5] Gibbson, G.G., Shett, P., 1994. Introduction to Drug Metabolism, 2nd Ed. Blackie Academic and Professional, London, p.217-221.

[6] Green, M.D., Tephly, T.R., 1996. Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein. Drug Metab. Dispos., 24(3):356-363.

[7] Honda, M., Nozawa, T., Igarashi, N., Inoue, H., Arakawa, R., Ogura, Y., Okabe, H., Taquchi, M., Hashimoto, Y., 2005. Effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Biol. Pharm. Bull., 28(8):1476-1479.

[8] Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193(1):265-275.

[9] Morgan, T., 1994. Clinical pharmacokinetics and pharmaco-dynamics of carvedilol. Clin. Pharmacokinet., 26(5):335-346.

[10] Nägele, H., Bohlmann, M., Eck, U., Petersen, B., Rodiger, W., 2000. Combination therapy with carvedilol and amiodarone in patients with severe heart failure. Eur. J. Heart Fail., 2(1):71-79.

[11] Nahrendorf, W., Rading, A., Steinig, G., van der Does, R., Schlote, A., 1992. A comparison of carvedilol with a combination of propranolol and isosorbide dinitrate in the chronic treatment of stable angina. J. Cardiovasc. Pharmacol., 19(Supp1. 1):114-116.

[12] Neugebauer, G., Neubert, P., 1991. Metabolism of carvedilol in man. Eur. J. Drug Metab. Pharmacokinet., 16(4):257-260.

[13] Neugebauer, G., Akpan, W., von Mollendorff, E., Neubert, P., Reiff, K., 1987. Pharmacokinetics and disposition of carvedilol in humans. J. Cardiovasc. Pharmacol., 10(Supp1. 11):85-88.

[14] Neugebauer, G., Akpan, W., Kaufmann, B., Reiff, K., 1990. Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound. Eur. J. Clin. Pharmacol., 38(Supp1. 2):108-111.

[15] Ohno, A., Saito, Y., Hanioka, N., Jinno, H., Saeki, M., Ando, M., Ozawa, S., Sawada, J., 2004. Involvement of human hepatic UGT1A1, UGT2B4, and UGT2B7 in the glucuronidation of carvedilol. Drug Metab. Dispos., 32(2):235-239.

[16] Oldham, H.G., Clarke, S.E., 1997. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(−)-carvedilol. Drug Metab. Dispos., 25(8):970-977.

[17] Packer, M., Bristow, M.R., Cohn, J.N., Colucci, W.S., Fowler, M.B., Gilbert , E.M., Shusterman, N.H., 1996. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med., 334(21):1349-1355.

[18] Radominska-Pandya, A., Czernik, P.J., Little, J.M., Battaglia, E., Mackenzie, P.I., 1999. Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab. Rev., 31(4):817-899.

[19] Ruffolo, R.R.Jr, Boyle, D.A., Venuti, R.P., Lukas, M.A., 1993. Preclinical and clinical pharmacology of carvedilol. J. Hum. Hypertens., 7(Suppl. 1):2-15.

[20] Saito, M., Kawana, J., Ohno, T., Kaneko, M., Mihara, K., Hanada, K., Suqita, R., Okada, N., Oosato, S., Naqayama, M., Sumiyoshi, T., Oqata, H., 2006. Enantioselective and highly sensitive determination of carvedilol in human plasma and whole blood after administration of the racemate using normal-phase high-performance liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 843(1):73-77.

[21] Schaefer, W.H., 1992. Formation of a carbamoyl glucuronide conjugate of carvedilol in vitro using dog and rat liver microsomes. Drug Metab. Dispos., 20(1):130-133.

[22] Sorich, M.J., McKinnon, R.A., Miners, J.O., Smith, P.A., 2006. The importance of local chemical structure for chemical metabolism by human uridine 5-diphosphate-glucuronosyltransferase. J. Chem. Inf. Model., 46(6):2692-2697.

[23] Sponer, G., Muller-Beckmann, B., 1983. Studies on the mechanisms on the vasodilating activity of BM 14190. Naungy-Schmiedeberg’s Archies of Pharmacology, 322(Suppl.):R46.

[24] Stahl, E., Henke, D., Mutschler, E., Spahn-Langguth, H., 1993. Saturable enantioselective first-pass effect for carvedilol after high oral racemate doses in rats. Archiv Der Pharmazie, 326(3):123-125.

[25] Takekuma, Y., Takenaka, T., Kiyokawa, M., Yamazaki, K., Okamoto, H., Kitabatake, A., Tsutsui, H., Suqawara, M., 2006. Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol. J. Pharm. Pharm. Sci., 9(1):101-112.

[26] Takekuma, Y., Takenaka, T., Kiyokawa, M., Yamazaki, K., Okamoto, H., Kitabatake, A., Tsutsui, H., Suqawara, M., 2007. Evaluation of effects of polymorphism for metabolic enzymes on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Biol. Pharm. Bull., 30(3):537-542.

[27] van Zwieten, P.A., 1993. Pharmacodynamic profile of carvedilol. Cardiology, 82(Suppl. 3):19-23.

[28] Xie, S.G., Chen, Y.K., Chen, S.Q., Zeng, S., 2006. Glucuronidation of apigenin by the recombinant human UGT1A3. Chin. J. Pharmacol. Toxicol., 20(5):405-409 (in Chinese).

[29] Yang, E., Wang, S., Kratz, J., Cyronak, M.J., 2004. Stereoselective analysis of carvedilol in human plasma using HPLC/MS/MS after chiral derivatization. J. Pharm. Biomed. Anal., 36(3):609-615.

[30] Yao, T.W., Zeng, S., 2001. Stereoselective determination of p-hydroxyphenyl-phenylhydantoin enantiomers in rat liver microsomal incubates by reversed-phase high-performance liquid chromatography using β-cyclodextrin as chiral mobile phase additives. Biomed. Chromatogr., 15(2):141-144.

[31] Yao, T.W., Zhou, Q., Zeng, S., 2000. Stereoselective determination of propafenone enantiomers in transgenic Chinese hamster CHL cells expressing human cytochrome P450. Biomed. Chromatogr., 14(7):498-501.

[32] Zeng, S., Zhong, J., Pan, L., Li, Y., 1999. HPLC separation and quantitation of ofloxacin enantiomes in rat microsomes. J. Chromatogr. B Biomed. Sci. Appl., 728(1):151-155.

[33] Zhou, H.H., Wood, A.J., 1995. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin. Pharmacol. Ther., 57(5):518-524.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE