OBJECTIVE To study the metabolic drug interactions of carvedilol with some commonly used chemical drugs for providing some useful information for clinic.METHODS Carvedilol was co-incubated with 42 commonly used drugs in rat liver microsomes and the concentrations of carvedilol glucuronides were determined by HPLC.The IC50 or Ki were calculated.RESULTS Felodipine,lacidipine,nitrendipine,simvastatin and lovastatin showed fairly strong inhibition on the glucuronidation of carvedilol in vitro,with Ki value between 0.65～63.48 μmol·L-1.The Ki values of the five drugs for carvedilol glucuronide M1 were lower than those for carvedilol glucuronide M2,as evidence of stronger inhibition for M1.Among these five drugs,lacidipine had the strongest inhibition,with the Ki value about 0.65 μmol·L-1 and 6.44 μmol·L-1 for M1 and M2,respectively.CONCLUSION There were strong interactions between the five drugs and carvedilol in vitro glucuronidation,the special attention should be paid when being co-administrated.
YOU Lin-y;ZENG Su.
In Vitro Metabolic Interaction between Carvedilol and Some Commonly Used Drugs [J]. Chinese Pharmaceutical Journal, 2008, 43(20): 1550-1554
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参考文献
[1] ZHO S，CHIANG D，CHIN R，et al. High-throughput screening of potential inhibitors for the metabolism of the investigational anti-cancer drug 5，6-dimethylxanthenone- 4-acetic acid[J] . J Chromatogr B Analyt Technol Biomed Life Sci，2002，767(1)：19-26.
[2] KIANG T K， ENSOM M H， CHANG T K. UDP-glucuronosy ltran- sferases and clinical drug-drug interactions[J] . Pharmacol Ther，2005，106(1)：97-132.
[3] BARIS N，KALKAN S，GUNERI S，et al. Influence of carvedilol on serum digoxin levels in heart failure：is there any gender difference[J] . Eur J Clin Pharmacol，2006，62(7)：535-538.
[4] AIBA T，ISHIDA K，YOSHINAGA M，et al. Pharmacokinetic characterization of transcellular transport and drug interaction of digoxin in Caco-2 cell monolayers[J] . Biol Pharm Bull，2005，28(1)：114-119.
[5] RATNAPALAN S，GRIFFITHS K，COSTEI A M，et al. Digoxin-carvedilol interactions in children[J] . J Pediatr，2003，142(5)：572-574.
[6] FUKUMOTO K，KOBAYASHI T，KOMAMURA K，et al. Stereo- selective effect of amiodarone on the pharmacokinetics of racemic carvedilol[J] . Drug Metab Pharmacokinet，2005，20(6)：423-427.
[7] BADER F M，HAGAN M E，CROMPTON J A，et al. The effect of beta-blocker use on cyclosporine level in cardiac transplant recipients[J] . J Heart Lung Transplant，2005，24(12)：2144-2147.
[8] KAIJSER M，JOHNSSON C，ZEZINA L，et al. Elevation of cyc- los porin A blood levels during carvedilol treatment in renal transplant patients[J] . Clin Transplant，1997，11(6)：577-581.
[9] HOKAMA N，HOBARA N，SAKAI M，et al. Influence of nica- rdipine and nifedipine on plasma carvedilol disposition after oral administration in rats[J] . J Pharm Pharmacol，2002，54(6)：821-825.
[10] GRAFF D W，WILLIAMSON K M，PIEPER J A，et al. Effect of fluoxetine on carvedilol pharmacokinetics，CYP2D6 activity，and autonomic balance in heart failure patients[J] . J Clin Pharmacol，2001，41(1)：97-106.
[11] YAO T W，HU Y Z. RP-HPLC Determination of diphenytriazol in rat liver microsomal incubates and its application in vitro metabolism[J] . Acta Pharm Sin(药学学报)，2002，37(6)：458-461.
[12] ZHU M，YAO T W，ZENG S. Glucuronidation and in vitro int- eraction of Ginkgo flavonoids with other drugs[J] . J Zhejiang Univ Sci B(浙江大学学报医学版)，2004，33(1)：15-20.
[13] ZENG S. Drug Metabolism(药物代谢学)[M] . Hangzhou：Zhejiang University Press，2004：180.
[14] FUJIMAKI M，SHINTANI S，HAKUSUI H. Stereoselective met- abolism of carvedilol in the rat. Use of enantiomerically radiolabeled pseudoracemates[J] . Drug Metab Dispos，1991，19(4)：749-753.
[15] CRESPI C L，STRESSER D M. Fluorometric screening for meta- bolism-based drug-drug interactions[J] . J Pharmacol Toxicol Methods，2000，44(1)：325-331.
[16] OLDHAM H G，CLARKE S E. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol[J] . Drug Metab Dispos，1997，25(8)：970-977.
[17] OHNO A，SAITO Y，HANIOKA N，et al. Involvement of human hepatic UGT1A1，UGT2B4，and UGT2B7 in the glucuronidation of carvedilol[J] . Drug Meab Dispos，2004，32(2)：235-239.
[18] BRESSLER R. Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs[J] . Geriatrics，2006，61(11)：12-18.
[19] HALLIDAY R C，JONES B C，SMITH D A，et al. An inves- tigation of the interaction between halofantrine，CYP2D6 and CYP3A4： studies with human liver microsomes and heterologous enzyme expression systems[J] . Br J Clin Pharmacol，1995，40(4)：369-378.
[20] OZDEMIR M，AKTAN Y，BOYDAG B S，et al. Interaction bet- ween grapefruit juice and diazepam in humans[J] . Eur J Drug Metab Pharmacokinet，1998，23(1)：55-59.
[21] KLOTZ U. Interaction potential of lercanidipine，a new vasoselective dihydropyridine calcium antagonist[J] . Arzneimittelforschung，2002，52(3)：155-161.
[22] MOLDEN E，AADERSSON K S. Simvastatin-associated rhabd- omyolysis after coadministration of macrolide antibiotics in two patients[J] . Pharmacotherapy，2007，27(4)：603-607.
[23] NEUVONEN P J，NIEMI M，BACKMAN J T. Drug interactions with lipid-lowering drugs： mechanisms and clinical relevance[J] . Clin Pharmacol Ther，2006，80(6)：565-581.
[24] MULDER A B，VAN LIJF H J，BON M A，et al. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin[J] . Clin Pharmacol Ther，2001，70(6)：546-551.
[25] TRANSON C，LEEMANN T，DAYER P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9，CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors[J] . Eur J Clin Pharmacol，1996，50(3)：209-215.
[26] TAKEDA S，ISHII Y，IWANAGA M，et al. Modulation of UDP-glucuronosyltransferase function by cytochrome P450： evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4[J] . Mol Pharmacol，2005，67(3)：665-672.
