Pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration

Lukša, J.; Josić, Dj.; Kremser, M.; Kopitar, Z; Milutinovic, Snezana

doi:10.1016/s0378-4347(97)00394-0

Cited by 54 publications

(29 citation statements)

References 11 publications

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“…Amlodipine plasma and serum levels have been detected by different methods such as thinlayer chromatography (LOQ = 2.0 ng/ml) [1], liquid chromatography with amperometric detection (LOQ = 0.2 ng/ml; RT = 8.5 min) [3], and liquid chromatography with ultraviolet detection (LOQ = 0.2 ng/ml; RT>40 min) [4]. Other methods such as capillary electrophoresis (LOQ = 5.0 ng/ml; RT = 9.8 min) [5], and gas chromatography (LOQ = 2.5 ng/ml; RT>9.0 min) [6] were also used to detect amlodipine plasma levels.…”

Section: Resultsmentioning

confidence: 99%

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Carvalho

Oliveira

Mendes³

et al. 2001

Biopharm & Drug Disp

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Section: Resultsmentioning

confidence: 99%

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Carvalho

Oliveira

Mendes³

et al. 2001

Biopharm & Drug Disp

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“…The following morning, subjects were given a single oral dose of 10-mg racemic amlodipine (Norvasc, Pfizer Pharmaceutical, Seoul, Korea). Blood samples were collected immediately prior to drug administration (baseline) and then at 1,2,3,4,5,6,7,8,9,10,12,24,48,72,96,120,144, and 168 h after drug administration. Blood samples were collected in heparinized tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) after discarding 1 ml of blood.…”

Section: Subjects and Study Designmentioning

confidence: 99%

“…5,6 Several studies revealed that the pharmacokinetics of amlodipine in humans is stereoselective. 4,7,8 The CYP3A subfamily is estimated to participate in the biotransformation of 50% of drugs known to undergo oxidative metabolism. 9 Four members of the CYP3A subfamily have been described in humans: CYP3A4, CYP3A5, CYP3A7, and CYP3A43.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, recently it has been reported that CYP3A5*3 genotype influences the pharmacokinetic characteristics of amlodipine racemate in humans. 16 Considering the evidence that CYP3A5 is involved in the disposition of amlodipine 1,16 and amlodipine disposition is stereoselective, 4,7,8 the substantial role of CYP3A5 might be expected in the stereoselective disposition of amlodipine in humans.…”

Section: Introductionmentioning

confidence: 99%

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Effect of cytochrome P450 3A53* genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Kim

Park

2008

Chirality

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Amlodipine is a racemic mixture composed of S- and R-form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10-mg amlodipine, enantiomers of amlodipine were analyzed using HPLC-MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S-amlodipine exhibited higher plasma levels than R-amlodipine in both genotype groups. S-amlodipine showed 15% higher mean peak plasma concentrations (Cmax) in CYP3A5*1/*3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P = 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P = 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R-amlodipine and S-amlodipine than CYP3A5*3/*3 carriers, respectively (for R-amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.234; for S-amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans.

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“…7 The drug displays an oral bioavailability of 50-80% with peak plasma concentrations at about 6-8 h. Amlodipine is extensively metabolized in the liver and slowly cleared with a terminal half live of 40-50 h. 4,8,9 After administration of the enantiomers of amlodipine as well as racemic amlodipine to healthy male volunteers, comparable pharmacokinetic parameters were reported for the amlodipine enantiomers but somewhat higher plasma concentrations were observed for the (S)-enantiomer. 10 In contrast, higher plasma concentrations of (R)-amlodipine than its (S)-enantiomer were reported in elderly hypertensive patients.…”

Section: Introductionmentioning

confidence: 96%

Stereoselective plasma protein binding of amlodipine

et al. 2009

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The binding of the (R)- and (S)-enantiomers of amlodipine to bovine serum albumin (BSA), human serum albumin (HSA), alpha(1)-acid glycoprotein (AGP), and human plasma (HP) was studied by equilibrium dialysis over the concentration range of 75-200 microM at a protein concentration of 150 microM. Unbound drug concentrations were determined by enantioselective capillary electrophoresis using 50 mM phosphate buffer, pH 2.5, containing 18 mM alpha-cyclodextrin as background electrolyte. Saturation of the protein binding sites was not observed over the concentration range tested. Upon application of racemic amlodipine besylate, (S)-amlodipine was bound to a higher extend by HSA and HP compared with (R)-amlodipine, whereas the opposite binding of the enantiomers was observed for BSA and AGP. Scatchard analysis was used to illustrate the different binding affinities of amlodipine besylate enantiomers to BSA, HSA and AGP.

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Pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration

Cited by 54 publications

References 11 publications

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Effect of cytochrome P450 3A53* genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Stereoselective plasma protein binding of amlodipine

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Pharmacokinetic behaviour of R-(+)- and S-(−)-amlodipine after single enantiomer administration

Cited by 54 publications

References 11 publications

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry

Effect of cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Stereoselective plasma protein binding of amlodipine

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Effect of cytochrome P450 3A53* genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects