Enantiomeric determination of amlodipine in human plasma by liquid chromatography coupled to tandem mass spectrometry

Streel, Bruno; Lainé, C; Zimmer, Collin; Sibenaler, R.; Ceccato, Attilio

doi:10.1016/s0165-022x(02)00133-1

Cited by 69 publications

(34 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, further studies would be needed to clarify partial inhibition by ketoconazole. Benidipine metabolism was also inhibited by azamulin, another CYP3A inhibitor (Streel et al, 2002). Correlations between the rate of benidipine metabolism and the activities of P450s in HLMs are summarized in Table 2.…”

Section: Identification Of Benidipine Metabolites In Hlmsmentioning

confidence: 99%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (؊)-␣ and (؉)-␣ isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CL int ) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (؊)-␣ isomer was similar to those from the (؉)-␣ isomer (1.9 ؎ 0.1 versus 2.3 ؎ 2.3 l/min/pmol P450 and 0.5 ؎ 0.2 versus 0.6 ؎ 0.6 l/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that the N-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL int values of CYP3A4-mediated metabolite formation from (؊)-␣ isomer were similar to those from (؉)-␣ isomer (17.7 versus 14.4 l/min/pmol P450, respectively). The total CL int values of CYP3A5-mediated metabolite formation from (؊)-␣ isomer were also similar to those from (؉)-␣ isomer (8.3 versus 11.0 l/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.Benidipine is a highly potent dihydropyridine calcium antagonist that is used clinically as a racemate. This agent shows slow onset and long-lasting antihypertensive and antianginal effects owing to the blockade of calcium ion entry to smooth muscle Yamada et al., 1990). It is currently in clinical use for the treatment of hypertension as a single daily medication (2-8 mg). Like other dihydropyridine calcium antagonists (except nifedipine and mepirodipine), benidipine has asymmetric carbons both in the 1,4-dihydropyridine ring and in the side chain of the benzylpiperidine ring. This drug is a racemate consisting of two optical isomers [(ϩ)-␣ and (Ϫ)-␣ isomer] of the four possible optical isomers because the other isomers are removed during the crystallization step on synthesis (Kobayashi and Kobayashi, 1998). The (ϩ)-␣ isomer was 30-to 100-fold more active than the (Ϫ)-␣ isomer in terms of the antihypertensive effect after i.v. administration to the spontaneously hypertensive rat (Muto et al., 1988).Pharmacokinetic studies in rats (Kobayashi and Kobayashi, 1998) and humans (Kobayashi et al., 1997) have shown that benidipine is we...

show abstract

Section: Identification Of Benidipine Metabolites In Hlmsmentioning

confidence: 99%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…HPLC [9][10][11] and LC-MS [12][13][14] for its determination in plasma/serum; HPLC 15) for its determination in human serum and pharmaceutical formulations; HPLC 16,17) ; HPTLC 18) for its determination in pharmaceuticals. Similarly, survey of literature for AML revealed methods based on spectrophotometry, 19) RP-HPLC 20) using fluorescence detection, HPLC-tandem mass spectrometry, 21,22) RP-HPLC using UV detection, 23,24) HPLC [25][26][27][28][29] in combination with other drugs, Flow injection analysis using UV-detection, 30) HPTLC, 31,32) stability indicating HPLC 33) and stability indicating HPLC 34) in combination with benazepril hydrochloride have been reported. Spectrophotometric 35) and HPLC 36) methods have been reported for simultaneous determination of ATV and AML, but these methods lack stability indicating nature.…”

Section: Atorvastatinmentioning

confidence: 99%

Stability Indicating RP-HPLC Method for Simultaneous Determination of Atorvastatin and Amlodipine from Their Combination Drug Products

2007

View full text Add to dashboard Cite

Atorvastatin 1) is a synthetic lipid lowering agent which inhibits HMG-CoA reductase and amlodipine 2) is a calcium antagonist drug effective in hypertension and angina pectoris. The combination drug product of atorvastatin (ATV) and amlodipine (AML) has recently been introduced in the market; co-administration of AML with ATV demonstrated statistically significant dose-related reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP) and LDL-C in patients with co-morbid hypertension and dyslipidemia. 3)Chemically ATV is [R-(R*,R*)]-2-(4-fluorophenyl)-b, dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2 : 1) trihydrate 4) and AML is 2-[(2-Aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester. 5)Stability testing forms an important part of the process of drug product development. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and enables recommendation of storage conditions, retest periods, and shelf lives to be established. The two main aspects of drug product that play an important role in shelf life determination are assay of active drug, and degradation products generated, during the stability study. The assay of drug product in stability test sample needs to be determined using stability indicating method, as recommended by the International Conference on Harmonization (ICH) guidelines 6) and USP-26. 7) Although stability indicating methods have been reported for assay of various drugs in drug products, most of them describe assay procedures for drug products containing only one active drug substance. Only few stability indicating methods are reported for assay of combination drug products containing two or more active drug substances. The objective of this work was to develop a simple, precise and rapid analytical LC procedure, which would serve as stability indicating assay method for combination drug product of ATV and AML.Both methods have been reported for simultaneous determination of ATV and AML, but these methods lack stability indicating nature. None of the reported analytical procedures describe a stability indicating method for simultaneous determination of ATV and AML in presence of their degradation products. This manuscript describes the development and validation of a stability indicating isocratic reversed-phase HPLC method for simultaneous determination of ATV and AML in presence of their degradation products as per ICH guidelines. The study describes development and subsequent validation of a stability indicating reverse-phase HPLC method for the simultaneous estimation of atorvastatin (ATV), and amlodipine (AML) from their combination drug product. The proposed RP-HPLC method utilizes a Lichrospher ® 100 C 18 , 5 m mm, 250 mm؋4.0 mm i.d. column, at ambient temperature, optimum ...

show abstract

“…For example, LC-MS or LC-MS/ MS is a method of choice for analysis of amplodipine, a dihydropyridine calcium channel blocker. [6][7][8] LC-MS analysis of ramipril in the plasma using enalapril maleate as the internal standard has been reported. 9 In this paper, we demonstrate that the LC-MS technique based on reversedphase separation and electrospray ionization mass spectrometry can be used with minimal sample pre-treatment to selectively determine and monitor enalapril in human plasma.…”

Section: Enalapril Maleate ((S)-1-{n-[1-(ethoxycarbonyl)-3-phenyl-mentioning

confidence: 99%

Determination of Enalapril in Human Plasma by High Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry

2004

Bulletin of the Korean Chemical Society

View full text Add to dashboard Cite

Revered-phase LC-electrospray ionization mass spectrometry was used to selectively determine enalapril from plasma with minimal sample preparation. Detection limit of the method was 1 ng/mL. Precision (within day and between days) and accuracy of the method at various concentrations were acceptable. The analytical technique was used for pharmacokinetic studies after administration of enalapril to human test subjects.

show abstract

Enantiomeric determination of amlodipine in human plasma by liquid chromatography coupled to tandem mass spectrometry

Cited by 69 publications

References 40 publications

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Stability Indicating RP-HPLC Method for Simultaneous Determination of Atorvastatin and Amlodipine from Their Combination Drug Products

Determination of Enalapril in Human Plasma by High Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry

Contact Info

Product

Resources

About