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

Saitō, Masako; Kawana, Junichi; Ohno, Tetsuro; Kaneko, Masahiro; Mihara, Kiyoshi; Hanada, Kazuhiko; Sugita, Ritsuko; Okada, Nozomi; OOSATO, S; Nagayama, Masatoshi

doi:10.1016/j.jchromb.2006.05.018

Cited by 36 publications

(27 citation statements)

References 9 publications

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“…[13][14][15] Assay of Carvedilol Enantiomers The amount of carvedilol in the samples was measured using chiral high performance liquid chromatography (HPLC) as described by Saito et al with minor modifications. [7][8][9][10]16) Briefly, carvedilol was extracted from the samples (0.1 ml) with 5 ml diethylether after alkalization in 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5). The organic phase was transferred and evaporated dry in a water bath at 45°C.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Horiuchi

Kato

Nakamura

et al. 2010

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist that has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmia. 1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of S-enantiomer with high b-blocking activity is approximately one-half of that of R-enantiomer with low b-blocking activity. 2,3) Both enantiomers are mostly eliminated by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 4) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways. 5) Oldham and Clarke reported that the oxidative metabolism of carvedilol is mediated by cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2 in microsomes from human lymphoblastoid cells expressing human CYP. 6) In addition, our previous findings indicated that R-carvedilol is metabolized mainly by CYP2D6 and partly by CYP1A2, 2C9, and 3A4, and that S-carvedilol is metabolized mainly by CYP1A2 and partly by CYP2C9, 2D6, and 3A4. 7-10) On the other hand, Ohno et al. found that uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol using microsomes from insect cells expressing human UGT. 11) In addition, they have demonstrated that glucuronidation of R-carvedilol is mediated by UGT1A1 and 2B4, and that glucuronidation of S-carvedilol is mediated by UGT2B7 and 2B4. 11) In 2005, Fukumoto et al. reported the effect of amiodarone on the stereoselective pharmacokinetics of carvedilol in patients with heart failure. 12) That is, they demonstrated that the mean serum concentration to dose (C/D) ratio of S-carvedilol in 54 patients who took amiodarone concomitantly with carvedilol was 2-fold higher than that in 52 patients who took carvedilol alone. On the other hand, there was no significant difference in the mean C/D values of R-carvedilol between the two groups. 12) They speculated that the oxidative metabolism of only S-carvedilol might be markedly inhibited by coadministration of amiodarone; however, the effects of amiodarone and/or its metabolite on the oxidation and glucuronidation of carvedilol enantiomers are still unresolved. 12) In the present study, to evaluate the mechanism responsible for the interaction between carvedilol and amiodarone, we investigated inhibitory and stimulative effects of amiodarone and desethylamiodarone on the metabolism of R-and S-carvedilol in human liver microsomes (HLM). The oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid (UDPGA). MATERIALS AND METHODS MaterialsCarvedilol was kindly supplied by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). NADPH was obtained from Kohjin Co., Ltd. (Tokyo, Japan). UDPGA trisodium salt, amiodarone hydrochloride, furafylline, sulfaphenazole, and quinidine hydrochloride...

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Section: Methodsmentioning

confidence: 99%

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Horiuchi

Kato

Nakamura

et al. 2010

Biological & Pharmaceutical Bulletin

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“…2,17) Briefly, whole blood samples (0.2 ml) were mixed with 0.5 ml of distilled water to hemolyze blood cells. After alkalinization with 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5), the samples were extracted with 5 ml of diethylether and back-extracted from the organic phase with 0.3 ml of 50 mM H 2 SO 4 .…”

Section: Subjects and Study Protocolmentioning

confidence: 99%

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Horiuchi

Nozawa

Fujii

et al. 2008

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist, clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.2) Carvedilol is metabolized extensively via aliphatic sidechain oxidation, aromatic ring oxidation, and conjugation pathways.3) Oldham and Clarke 4) reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. In addition, Ohno et al. 5) reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. In the previous study, we examined the effect of CYP2D6*10, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 on the pharmacokinetics of carvedilol in 54 Japanese volunteers. 2,6) The oral clearance (CL/F) and also volume of distribution (V/F) of R-and S-carvedilol were significantly lower in subjects with the CYP2D6*10 allele than those with CYP2D6*1/*1, *1/*2, or *2/*2 genotype, indicating that the systemic clearance (CL) and/or bioavailability (F) of both enantiomers is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 did not affect the pharmacokinetics of R-and S-carvedilol in healthy Japanese. 2,6) Several pharmacokinetic studies have suggested that hepatic elimination of certain drugs via oxidative metabolism is impaired in patients with heart failure (HF) [7][8][9][10][11][12][13] ; that is, the CL/F value of prazosin after oral administration in HF patients was 46% of that in healthy subjects.7) It was also reported that the CL/F value of aminopyrine after oral administration in HF patients in the aminopyrine breath test was 24% of that in control subjects. 8) In addition, CL values of midazolam and quinidine (CYP3A4 substrates) after intravenous administration were decreased by 32% and 33% in HF patients, respectively. 9,10) The CL value of theophylline (CYP1A2 substrate) after intravenous administration was markedly decreased in HF patients. 11,12) Recently, population pharmacokinetic analysis has revealed that the CL/F value of mexiletine, which is mainly metabolized by CYP1A2 and CYP2D6, is reduced significantly in HF patients as compared with non-HF patients.13) However, it is still unclear whether the pharmacokinetics of R-and/or S-carvedilol is altered by HF. In the present study, therefore, we investigated the pharmacokinetics of R-and S-carvedilol in routinely treated Japanese patients with HF. MATERIALS AND METHODS Subjects and Study ProtocolTwenty-four Japanese patients with HF (16 men and 8 women) participated in this study. Their age was between 45 and 91 years old (70.5Ϯ11.3 years), and their body weight was between 36...

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“…Reverse-phase (RP)-HPLC methods were described for the analysis of Carvedilol racemate 1, 3-5, 8, 9 or carvedilol enantiomers using chiral derivatization 2,10 . HPLC methods using a chiral stationary phase have been reported for the analysis of carvedilol enantiomers 6,7 . The clean-up procedures for the extraction of carvedilol from biological matrix consist of protein precipitation 5,6,10,12 , solid-phase extraction (SPE) 2,3,9 , liquid-liquid extraction (LLE) 6,7,[11][12][13] , combinations of protein precipitation with SPE 4 or combinations of LLE with back-extraction 1,8 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of Carvedilol and Its Metabolite in Human Plasma Using Liquid Chromatography Coupled with Tandem Mass Spectrometry

Janjanam¹,

Bimireddy²

2017

IJPTR

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: A rapid, sensitive and selective method for the determination of Carvedilol and its metabolite in human plasma was developed using liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Carvedilol, its metabolite 4-OH carvedilol and abacavir (internal standard) were extracted from human plasma by solid phase extraction technique (SPE) and analyzed on an Discovery column (C8, 50 × 4.6 mm, 5µ) with the mobile phase of acetonitrile -0.1% formic acid in water (70:30 v/v). The analytes were detected using an electro spray ionization tandem mass spectrometry in the multiple reaction monitoring mode. The standard curve was linear (r = 0.9998) over the concentration range of 0.5-100 ng/mL and 0.3-40 ng/mL for carvedilol and 4-OH carvedilol respectively. The lower limit of quantification for carvedilol was 0.5 ng/mL and 0.3 ng/mL for carvedilol and 4-OH carvedilol respectively using 500 µL plasma samples. The coefficient of variation and relative error for intra-and inter-assay at four QC levels were 3.37 to 9.53 %, 4.76 to 7.01% and 3.31 to 6.91%, 5.23 to 6.64 % respectively. The matrix effect for carvedilol, 4-OH carvedilol and abacavir were practically absent. The extraction recoveries of carvedilol, 4-OH carvedilol and abacavir were 78.90, 83.25 and 85.20%, respectively.

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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

Cited by 36 publications

References 9 publications

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Analysis of Carvedilol and Its Metabolite in Human Plasma Using Liquid Chromatography Coupled with Tandem Mass Spectrometry

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