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Zolpidem is extensively metabolized by CYP3A4, CYP2C9 and CYP1A2. Previous studies demonstrated that pharmacokinetics of zolpidem was affected by CYP inhibitors, but not by short-term treatment of clarithromycin. The objective of this study was to investigate the effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. In the control phase, 33 subjects received a single dose of zolpidem (5 mg). One week later, in the clarithromycin phase, the subjects received clarithromycin (500 mg) twice daily for 5 days to reach steady state concentrations, followed by zolpidem (5 mg) and clarithromycin (500 mg). In each phase, plasma concentrations of zolpidem were evaluated up to 12 h after drug administration by using liquid chromatography-tandem mass spectrometry method. In the clarithromycin phase, mean total area under the curve of zolpidem (AUCinf) was 1.62-fold higher and the time to reach peak plasma concentration of zolpidem (tmax) was prolonged by 1.95-fold compared to the control phase. In addition, elimination half-life (t1/2) of zolpidem was 1.40-fold longer during co-administration with clarithromycin and its apparent oral clearance (CL/F) was 36.2% lower with clarithromycin administration. The experimental data demonstrate the significant pharmacokinetic interaction between zolpidem and clarithromycin at steady-state.

Zolpidem is indicated for the short-term treatment of insomnia and it is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C19, CYP1A2, and CYP2C9. Therefore, we evaluated the effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of zolpidem in healthy male subjects. Thirty-two male subjects were recruited and all subjects were classified into three groups according to their genotypes: CYP2C19EM (CYP2C19*1/*1, n = 12), CYP2C19IM (CYP2C19*1/*2 or *1/*3, n = 10), and CYP2C19PM (CYP2C19*2/*2, *2/*3 or *3/*3, n = 10). The pharmacokinetic parameters of zolpidem were compared in three CYP2C19 genotype groups after zolpidem administration with or without a CYP3A4 inhibitor at steady-state concentration. Plasma concentrations of zolpidem were determined up to 12 h after drug administration by liquid chromatography-tandem mass spectrometry method. The maximum plasma concentration (Cmax) differed, but mean total area under the plasma concentration–time curve (AUCinf), half-life (t1/2), and apparent oral clearance (CL/F) of zolpidem administered alone did not significantly differ among the three different CYP2C19 genotype groups. Furthermore, when zolpidem was administered with a CYP3A4 inhibitor at steady-state concentration, there were no significant differences in any of the pharmacokinetic parameters of zolpidem in relation to CYP2C19 genotypes. In conclusion, we did not find any evidence for the impact of CYP2C19 genetic polymorphisms on the pharmacokinetic parameters of zolpidem.

Tamsulosin, a selective antagonist of the α1-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2 mg oral dose of tamsulosin. After a washout period of 1 week, on day 8, the subjects were given a 60 mg oral dose of diltiazem three times daily for four days. On day 10, 1 h after the morning dose of diltiazem, they received a single 0.2 mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the Cmax and AUCinf of tamsulosin in each CYP2D6 genotype group were significantly increased (p

Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n = 8; *wt = *1 or *2), CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6). Concentrations of clomiphene and its metabolites were determined using a validated HPLC–MS/MS analytical method in plasma samples collected up to 168 h after the drug intake. There was a significant difference only in the Cmax of clomiphene between three CYP2D6 genotype groups (p

Tolterodine, a nonselective muscarinic antagonist available only as immediate release (IR) or extended release (ER) oral formulations, is used for the treatment of overactive bladder (OAB). This study aimed to compare the efficacy and extent of dry mouth adverse effects of tolterodine transdermal patch to the oral formulation. The two formulations have been examined through the muscarinic receptor binding tests conducted in bladder and salivary gland tissues and the salivary secretion tests conducted in rats. Comparable average tolterodine blood concentration levels were obtained 3 h after oral administration of tolterodine 25 mg/kg and 12 h after transdermal application of tolterodine patch 6 mg/8 cm2. While Kd in the bladder tissue increased to a similar degree in both formulations of tolterodine, Kd in the salivary gland increased to a greater degree in the oral formulation. These results indicate that similar degree of inhibitory effects were observed in the bladder for both formulations while less inhibitory effects were observed in the salivary gland with tolterodine transdermal formulation compared to the oral formulation. For assessment of salivary secretion, tolterodine transdermal patch 6 mg/8 cm2 application resulted in significantly less inhibitory effects than oral tolterodine 25 mg/kg. Therefore, this study suggests that tolterodine transdermal patch could be a useful formulation that provides uniform and consistent inhibitory effects to effectively control OAB symptoms with reduced severity of dry mouth in comparison to the oral formulation.

Tolterodine is a nonselective muscarinic antagonist that is indicated for the overactive urinary bladder and other urinary difficulties. We developed and validated a simple, rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (LC-MS/MS) for the quantitation of tolterodine and its major metabolites, 5-hydroxymethyltolterodine (5-HMT) and N-dealkyltolterodine (NDT), in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of the three analytes was achieved using a reversed-phase Luna Phenyl-hexyl column (100 × 2.0 mm, 3 μm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in electrospray ionization (ESI) positive ion mode. The retention time of tolterodine, 5-HMT, NDT, and internal standard (IS) were 1.4, 1.24, 1.33, and 1.26 min, respectively. The calibration curves were linear over a range of 0.025-10 ng/ml for tolterodine and 5-HMT, and 0.05-10 ng/ml for NDT. The lower limit of quantifications using 200 μl of human plasma was 0.025 ng/ml for tolterodine and 5-HMT, and 0.05 ng/ml for NDT. The mean accuracy and precision for intra- and inter-run validation of tolterodine, 5-HMT, and NDT were all within acceptable limits. These results showed that a simple, rapid and sensitive LC-MS/MS method for the quantification of tolterodine and its major metabolites in human plasma was developed. This method was successfully applied to a pharmacokinetic study in humans.

Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, is used for the treatment of rheumatoid arthritis and osteoarthritis. The predominant hepatic metabolism of celecoxib to celecoxib carboxylic acid (CCA) is mediated mainly by CYP2C9. We investigated the effects of the major CYP2C9 genetic variants in Asian populations, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in healthy Korean subjects. A single 200-mg oral dose of celecoxib was given to 52 Korean subjects with different CYP2C9 genotypes: CYP2C9EM (n = 26; CYP2C9*1/*1), CYP2C9IM (n = 24; CYP2C9*1/*3 and *1/*13), and CYP2C9PM (n = 2; CYP2C9*3/*3). Celecoxib and CCA concentrations in plasma samples collected up to 48 or 96 h after drug intake were determined by HPLC–MS/MS. The mean area under the plasma concentration–time curve (AUC0–∞) of celecoxib was increased 1.63-fold (P

Tolterodine is metabolized to an active 5-hydroxymethyl tolterodine (5-HMT) by CYP2D6. This study investigated the relationship between CYP2D6 genotypes and pharmacokinetics of tolterodine and its active metabolite in healthy Korean subjects. All volunteers were genotyped for CYP2D6 and divided into four different genotype groups (CYP2D6*wt/*wt [*wt = *1 or *2], CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10). Each subject received a single oral dose of tolterodine tartrate (2 mg) in single-dose phase of the study. After the single-dose phase of the study, the same subjects received a single oral dose of tolterodine tartrate (2 mg) once daily for 1 week during multiple-dose tolterodine administration phase. Plasma concentrations of tolterodine and 5-HMT were measured by using liquid chromatography-tandem mass spectrometry method. Our study demonstrated that plasma exposure of tolterodine in CYP2D6*10/*10 and CYP2D6*5/*10 group significantly increased, compared with CYP2D6*wt/*wt group (P

Zolpidem is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C9, CYP1A2, CYP2D6 and CYP2C19. The aim of this study was to identify the effects of CYP2C9*3 allele on the pharmacokinetics of zolpidem. Healthy male subjects were divided into two genotype groups, CYP2C9*1/*1 and CYP2C9*1/*3. They received a single oral dose of 5 mg zolpidem, and the plasma concentrations of zolpidem were determined up to 12 h after drug administration. In addition, since zolpidem is metabolized at a high rate by CYP3A4, the effect of CYP2C9*3 allele on the pharmacokinetics of zolpidem was also observed in the condition where CYP3A4 was sufficiently inhibited by the steady-state concentration of clarithromycin, a potent CYP3A4 inhibitor. For this, clarithromycin 500 mg was administered twice daily for 5 days. Plasma concentrations of zolpidem were determined using liquid chromatography-tandem mass spectrometry method. The overall pharmacokinetic parameters of zolpidem were not significantly different between two CYP2C9 genotypes. Even with the potent CYP3A4 inhibitor clarithromycin present at steady-state concentrations, there were no significant differences in the exposure of zolpidem, except for elimination half-life (t1/2). In conclusion, our study suggests that CYP2C9*1/*3 genotype does not affect the plasma exposure of zolpidem.

The effects of CYP2C9*1/*3 and *3/*3 genotypes on the pharmacokinetics and pharmacodynamics of meloxicam were evaluated in healthy Korean subjects.After oral administration of 15 mg meloxicam, the plasma concentrations of meloxicam were assessed in 11 CYP2C9*1/*1 individuals, eight CYP2C9*1/*3 individuals, and three CYP2C9*3/*3 individuals. The pharmacodynamic effects were determined by measuring thromboxane B2 generated in blood.A nine-fold lower apparent oral clearance and an eight-fold higher AUC0-∞ of single-dose meloxicam were observed in CYP2C9*3/*3 individuals when compared with CYP2C9*1/*1 individuals. CYP2C9*3/*3 individuals also showed markedly increased inhibition of thromboxane B2 generation by meloxicam.These results indicate that CYP2C9*3/*3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.

To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC–MS/MS. For atomoxetine, the Cmax, AUC0–∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0–∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0–∞ was not different between these groups. The Cmax, AUC0–∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

Zolpidem (ZPD) is widely described for the short-term treatment of insomnia. We have developed and validated a simple and rapid liquid chromatography analytical method using tandem mass spectrometry (LC-MS/MS) for the quantification of ZPD in human plasma. Using dibucaine as an internal standard (IS), the analyte was extracted with methyl t-butyl ether (MTBE). Chromatographic separation of ZPD was performed on a reversed-phase Luna C18 column (50 mm × 2.0 mm i.d., 5 μm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.0)-methanol (15:85, v/v) at a flow rate of 250 μm/min. The total run-time was 2.5 min and the retention times of ZPD and IS were 0.66 and 0.74 min, respectively. The mass-to-charge transition monitored for quantification of ZPD and IS was 308.2→235.2 and 344.0→271.0, respectively. The lower limit of quantification (LLOQ) using 100 μL of human plasma was 0.05 ng/mL and the calibration curves were linear over a range of 0.05-200 ng/mL (r(2)>0.9964). The mean accuracy and precision for intra- and inter-run validation of ZPD were within acceptable limits. In the present LC-MS/MS method, we showed improved sensitivity for quantification of the ZPD in human plasma using lower volume of plasma compared with previously described analytical methods for ZPD. This validated method was successfully applied to a pharmacokinetic study in humans.

The aim of this study was to investigate the impact of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen and its metabolite. The CYP2C9 genotypes were determined with the use of polymerase chain reaction and restriction fragment and DNA sequencing analysis in 358 healthy Koreans. Among them, twenty individuals with CYP2C9*1/*1 (n = 12) or CYP2C9*1/*3 (n = 8) genotypes received a single 40 mg oral dose of flurbiprofen. The plasma concentrations of flurbiprofen and its metabolite, 4′-hydroxyflurbiprofen were measured by HPLC. AUCinf of flurbiprofen was significantly higher and its clearance was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. The AUC ratio of 4'-hydroxyflurbiprofen to flurbiprofen was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. These results indicate that the individuals carrying of CYP2C9*3 have significant reduction in flurbiprofen metabolism. The clinical use of this information may allow for more efficient personalized pharmacotherapy.

Flurbiprofen (FLB) is one of the phenylalkanoic acid derivatives of non-steroidal anti-inflammatory drugs used for the management of pain and inflammation in patients with arthritis. We developed and validated a rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of FLB and its major metabolite, 4'-hydroxyflurbiprofen (4'-OH-FLB), in human plasma. Probenecid was used as an internal standard (IS). After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of the two analytes was achieved using a reversed-phase Luna C18 column (2.0mm×50mm, 5μm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.5)-methanol (15:85, v/v) and quantified by MS/MS detection in ESI negative ion mode. The flow rate of the mobile phase was 250μl/min and the retention times of FLB, 4'-OH-FLB, and IS were 1.1, 0.8, and 0.9min, respectively. The calibration curves were linear over a range of 0.01-10μg/ml for FLB and 0.01-1μg/ml for 4'-OH-FLB. The lower limit of quantifications using 100μl of human plasma was 0.01μg/ml for both analytes. The mean accuracy and precision for intra- and inter-run validation of FLB and 4'-OH-FLB were all within acceptable limits. The present HPLC-MS/MS method showed improved sensitivity for quantification of the FLB and its major metabolite in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans.

Tamsulosin, a selective α₁-adrenoceptor antagonist, is used for the treatment of benign prostatic hyperplasia (BPH). We developed and validated a rapid, sensitive, and simplified liquid chromatography analytical method utilizing tandem mass spectrometry (LC-MS/MS) for the determination of tamsulosin in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of tamsulosin was achieved using a reversed-phase Luna C₁₈ column (2.0 mm × 50 mm, 5 μm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (25:75, v/v) and quantified by MS/MS detection in ESI positive ion mode. The flow rate of the mobile phase was 200 μL/min and the retention times of tamsulosin and the internal standard (IS, diphenhydramine) were 0.8 and 0.9 min, respectively. The calibration curves were linear over a range of 0.01-20 ng/mL (r>0.999). The lower limit of quantification using 500 μL of human plasma was 0.01 ng/mL. The mean accuracy and precision for intra- and inter-day validation of tamsulosin were both within acceptable limits. The present LC-MS/MS method showed improved sensitivity for quantification of tamsulosin in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans.