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ABSTRACT: Enalapril is an angiotensin-converting enzyme (ACE) inhibitor approved for the treatment of mild to severe hypertension and congestive heart failure. There is evidence that enalapril may be an organic anion-transporting polypeptide 1B1 (OATP1B1) substrate, suggesting that genetic polymorphisms of the OATP1B1 gene may play a role in causing the interindividual pharmacokinetic differences of this drug.
The purpose of this study was to investigate the functional significance of the OATP1B1 genetic polymorphism on the pharmacokinetics of enalapril and its active metabolite enalaprilat in healthy Chinese adult male participants.
This was a single-center, open-label, single- and multiple-dose study conducted in healthy Chinese male participants. Each participant received a single oral dose of 10 mg enalapril under fasting conditions, followed by enalapril 10 mg/d for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 24 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7; on day 7, samples were collected from 0 to 72 hours after drug administration. An HPLC-MS/MS method was used to determine plasma concentrations of enalapril and enalaprilat. A polymerase chain reaction technique was used for genotyping of 2 single nucleotide polymorphisms (SNPs) of the OATP1B1 gene: T521C and A388G. The pharmacokinetic parameters of enalapril and enalaprilat were then compared according to genotype groups, using 1-way ANOVA, except for T(max) in which the Mann-Whitney test or Kruskal-Wallis test was used.
The study included 32 healthy Han Chinese male participants (age range, 18-28 years; weight range, 50.0-80.0 kg; height range,159-182.0 cm). Twenty-six were OATP1B1*15 noncarriers (homozygous for 521TT), the others were *15 carriers with at least one 521 T>C mutant allele. After single and multiple oral doses of 10 mg enalapril, plasma concentrations of enalapril in *15 noncarriers were lower than that in *15 carriers, with significant difference in area under the curve at steady state (AUC(ss)) between *15 noncarriers and *15 carriers (P = 0.048) in the multiple-dose phase. There were no significant differences in enalapril's AUC(0-24), C(max), or the ratio of the AUC(0-24h) in the single-dose study to the AUC(ss) (R(ac)) between the *15 carriers and noncarriers. In contrast to enalapril, the mean AUC(0-24h) and C(max) of enalaprilat in *15 noncarriers was significantly higher than those in *15 carriers (P = 0.040 and P = 0.027, respectively) in the single-dose phase. There were no significant differences in enalaprilat's AUC(ss) or C(maxss) between the 2 groups in the multiple-dose phase. For the 3 groups classified according to the effect of A388G variant in all subjects homozygous for 521T (TT), *1a/*1a, *1a/*1b, and *1b/*1b, no significant difference was found in AUC(0-24h), C(max), and T(max) of enalapril and enalaprilat.
In this small population of healthy Chinese men, the OATP1B1*15 allele and T521C variant appeared to be an important determinant of the pharmacokinetics of enalapril. There were significant differences between the *15 carriers and noncarriers in enalapril's AUC(ss) and enalaprilat's AUC(0-24h), C(max), and R(ac). However, there were no significant differences in enalapril's AUC(0-24), C(max), or enalaprilat's AUC(ss), C(maxss) between the *15 carriers and noncarriers.
Clinical Therapeutics 05/2011; 33(5):655-63. · 2.32 Impact Factor
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ABSTRACT: The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men.
This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nons-moking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests.
The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean t(1/2) for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean T(max) was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean C(max) was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) microg/L; and mean AUC(last) was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) microg . h/L. There were no significant differences in any PK parameter between dose groups. For M-1, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for t(1/2); 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for T(max); 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) microg/L for C(max); and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) microg . h/L for AUC(last). Only dose-normalized Cmax and AUC(last) differed significantly between dose groups (P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for t(1/2), T(max), C(max), and AUC(0-infinity) for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) microg/L, and 13.8 (3.6) microg . h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUC(last) (P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) microg/L, and 381.8 (161.2) microg . h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug.
The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated.
Clinical Therapeutics 07/2008; 30(7):1290-9. · 2.32 Impact Factor
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ABSTRACT: A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with electrospray ionization (ESI) was developed and validated for the simultaneous determination of pitavastatin and its lactone in human plasma and urine. Following a liquid-liquid extraction, both the analytes and internal standard racemic i-prolact were separated on a BDS Hypersil C(8) column, using methanol-0.2% acetic acid in water (70: 30, v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 422.4-->m/z 290.3 for pitavastatin, m/z 404.3-->m/z 290.3 for pitavastatin lactone and m/z 406.3-->m/z 318.3 for the internal standard, respectively. Linear calibration curves of pitavastatin and its lactone were obtained in the concentration range of 1-200 ng/ml, with a lower limit of quantitation of 1 ng/ml. The intra- and inter-day precision values were less than 4.2%, and accuracies were between -8.1 and 3.5% for both analytes. The proposed method was utilized to support clinical pharmacokinetic studies of pitavastatin in healthy subjects following oral administration.
Journal of Chromatography B 04/2008; 865(1-2):127-32. · 2.89 Impact Factor
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ABSTRACT: Atrial flutter is a common sustained atrial tachyarrhythmia whose frequency increases with age. Ibutilide is a class III antiarrhythmic agent used for the cardioversion of atrial flutter or atrial fibrillation.
This study assessed the pharmacokinetic (PK) and pharmacodynamic properties and tolerability of a single intravenous dose of ibutilide fumarate in healthy Chinese men.
This Phase I, randomized, open-label, increasing-dose trial was conducted at the Clinical Pharmacology Center, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking men aged 18 to 45 years and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 6 treatment groups: ibutilide 0.005, 0.01, or 0.02 mg/kg, or 0.5, 0.75, or 1.0 mg. Each volunteer received a 10-minute infusion of ibutilide under fasting conditions. For analysis of PK properties, blood samples were obtained at the following times: immediately before administration of study drug; 3, 5, 8, 10, 30, and 60 minutes after administration; and 2, 4, 6, 8, 12, and 24 hours after administration. Plasma ibutilide concentrations were determined using a validated high- performance liquid chromatography method with tandem mass-spectrometric detection. Continuous electrocardiographic monitoring was performed, and 12-lead electrocardiograms were recorded before dosing and at defined times from the start of infusion until 24 hours after dosing. Tolerability was assessed throughout the study based on physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse effects.
Forty healthy Chinese men were enrolled (mean [SD] age, 24.0 [3.9] years [range, 19-36 years]; mean [SD] body weight, 62.8 [7.9] kg [range, 48- 80 kg]). The plasma ibutilide end-of-infusion concentration and AUC(0-infinity) increased approximately linearly with increasing doses of ibutilide. No statistically significant differences in the principal PK parameters were found among dosage groups; t(1/2) ranged from 7.5 to 9.1 hours, systemic clearance from 68 to 85 mL/min per kg, and Vd from 51 to 60 L/kg. The mean QTc interval was significantly increased during and after ibutilide infusion (baseline range, 406-418 milliseconds; maximum range, 469-683 milliseconds; P < 0.05 vs baseline). The changes in QTc interval were dose dependent, and there was a significant correlation between plasma ibutilide concentrations and changes in the QTc interval (r = 0.7244; P < 0.01). There were no significant changes in blood pressure or the QRS and PR intervals. One volunteer complained of dizziness, but no other apparent adverse effects were observed.
The results of this study in a selected population of healthy Chinese men suggest that the PK properties of ibutilide are linear with respect to dosing. A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration- dependent manner. Ibutilide was generally well tolerated.
Clinical Therapeutics 09/2007; 29(9):1957-66. · 2.32 Impact Factor
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ABSTRACT: A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with positive electrospray ionization (ESI) was developed for the quantification of ranolazine in human plasma. After liquid-liquid extraction of ranolazine and internal standard (ISTD) phenoprolamine from a 100 microl specimen of plasma, HPLC separation was achieved on a Nova-Pak C(18) column, using acetonitrile-water-formic acid-10% n-butylamine (70:30:0.5:0.08, v/v/v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 428.5-->m/z 279.1 for ranolazine and m/z 344.3-->m/z 165.1 for the internal standard, respectively. Linear calibration curves were obtained in the concentration range of 5-4000 ng/ml, with a lower limit of quantitation (LLOQ) of 5 ng/ml. The intra- and inter-day precision values were below 3.7% and accuracy was within +/-3.2% at all three quality control (QC) levels. This method was found suitable for the analysis of plasma samples collected during the phase I pharmacokinetic studies of ranolazine performed in 28 healthy volunteers after single oral doses from 200 mg to 800 mg.
Journal of Chromatography B 02/2007; 846(1-2):346-50. · 2.89 Impact Factor
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ABSTRACT: A simple, sensitive and rapid high-performance liquid chromatography/negative electrospray ionization tandem mass spectrometry method was developed and validated for the assay of aranidipine (AR) and its active metabolite (AR-M) in human plasma. Following a liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reversed-phase column and analyzed by mass spectrometry in the multiple reaction monitoring mode using the respective [M-H]- ions, m/z 387.0 --> 164.0 for AR, m/z 389.1 --> 208.1 for AR-M and m/z 359.0 --> 121.8 for the internal standard. The assay exhibited a linear dynamic range of 0.02-10 ng x mL(-1) for AR and 0.2-100 ng x mL(-1) for AR-M in human plasma. The limits of quantitation were 0.02 ng x mL(-1) for AR and 0.2 ng x mL(-1) for AR-M. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.8 min for each sample exhibited its high-throughout analysis ability. The validated method can be applied to analyze human plasma samples for pharmacokinetic studies.
Rapid Communications in Mass Spectrometry 01/2006; 20(19):2871-7. · 2.79 Impact Factor
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ABSTRACT: A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed and validated for determination of ibutilide in human plasma. The analyte and internal standard sotalol were extracted from plasma samples by liquid-liquid extraction, and separated on a C(18) column, using acetonitrile-water-10% butylamine-10% acetic acid (80:20:0.07:0.06, v/v/v/v) as the mobile phase. Detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via TurboIonSpray ionization (ESI). Linear calibration curves were obtained in the concentration range of 20-10,000 pg/ml, with a lower limit of quantitation of 10 pg/ml. The intra- and inter-day precision values were below 8% and accuracy was within +/-3% at all three QC levels. The method was utilized to support clinical pharmacokinetic studies of ibutilide in healthy volunteers following intravenous administration.
Journal of Chromatography B 03/2005; 816(1-2):81-5. · 2.89 Impact Factor
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ABSTRACT: Growth factor signaling by receptor tyrosine kinases regulates several cell fates, such as proliferation and differentiation. Sef was genetically identified as a negative regulator of fibroblast growth factor (FGF) signaling. Using bioinformatic methods and rapid amplification of cDNA ends-PCR, we isolated both the mouse and the human Sef genes, which encoded the Sef protein and Sef-S isoform that was generated through alternative splicing. We provide evidence that the Sef gene products were located mainly on the cell membrane. Co-immunoprecipitation and immunostaining experiments indicate that hSef interacts with FGFR1 and FGFR2 but not FGFR3. Our results demonstrated that stably expressed hSef strongly inhibits FGF2- or nerve growth factor-induced PC-12 cell differentiation. The intracellular domain of hSef is necessary for the inhibitory effect on FGF2-induced PC-12 cell differentiation. Furthermore, our data suggested Sef exerted the negative effect on FGF2-induced PC-12 cell differentiation through the prevention of Ras-mitogen-activated protein kinase signaling, possibly functioning upstream of the Ras molecule. These findings suggest that Sef may play an important role in the regulation of PC-12 cell differentiation.
Journal of Biological Chemistry 01/2004; 278(50):50273-82. · 4.77 Impact Factor
