Kyung-Sang Yu

Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

Pitavastatin is a potent, newly developed 3‐hydroxy‐3‐methylglutaryl–coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 (OATP1B1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin.

A variant 2677A allele of the MDR1 gene affects fexofenadine disposition

There have been considerable disagreements regarding the influence of MDR1 (ABCB1) polymorphisms on the disposition of P‐glycoprotein (P‐gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDR1 gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics.

Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states

Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions.

Effect of the UGT2B15 Genotype on the Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Intravenous Lorazepam in Healthy Volunteers

Our objective was to investigate the effect of the uridine 5′‐diphosphate‐glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers.

Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19

Moclobemide, an antidepressant with selective monoamine oxidase‐A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study.

Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects.

Pharmacokinetic and pharmacodynamic profiles of lorazepam and valproate were analyzed according to uridine 5′‐diphosphate‐glucuronosyltransferase (UGT)2B7 genotype in 14 healthy subjects with UGT2B15*2/*2 genotype. Systemic clearance of lorazepam (2 mg intravenously) and area under the concentration–time curve (AUC) of valproate (600 mg once daily for 4 days) were analyzed as pharmacokinetic parameters, and area under the effect–time curve (AUEC) of psychomotor coordination tests (Vienna) was used for pharmacodynamic parameter. No significant differences were found in systemic clearances of lorazepam by UGT2B7 genotype. AUCs of valproate showed an increasing tendency as the number of UGT2B7*2 alleles increased, but the difference was insignificant. Psychometric results were significant among the UGT2B7 genotype group (AUEC_tracking 261.5±298.9 in *1/*1, and 3,396.8±947 in *2/*2, P=0.047) when the two drugs were coadministered. Our study suggests that the UGT2B7 genotype probably affects lorazepam–valproate pharmacodynamic interaction, especially in subjects who have homovariant genotypes of UGT2B7 and UGT2B15, although the effects on the pharmacokinetics are less significant.

Lack of association between ABCB1, ABCG2, and ABCC2 genetic polymorphisms and multidrug resistance in partial epilepsy

ATP-binding cassette (ABC) transporters participate in drug disposition and response in various conditions, and many polymorphisms in ABC transporter genes have been recognized in association with altered transporter functions of various drugs. Studies on epilepsy have focused on the C3435T polymorphism of the ABCB1 gene, but other ABC transporters are also thought to be involved in the transport of antiepileptic drugs. We have evaluated the functional polymorphisms of ABCB1, ABCG2, and ABCC2 genes with regard to epilepsy drug response in partial epilepsy, and have investigated the potential of combined effects of polymorphisms in more than one transporter gene. We studied 6 genetic polymorphisms in 3 transporter genes in 193 drug responders and 198 nonresponders. There was no significant difference between the two groups, and we did not observe any combined effects of ABCB1 and ABCG2 genetic polymorphisms. Our study suggests that genetic polymorphisms in ABC transporters may not be significant predictors of drug response in epilepsy patients.

Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single‐blind, randomized, placebo‐controlled, dose‐rising, parallel‐group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple‐dose groups of 150 mg and 300 mg (once‐daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple‐dose study was conducted separately after the single‐dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single‐dose administration and then declined monoexponentially with a terminal half‐life (t1/2) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single‐dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose‐related pharmacological effects were obvious for dose groups of 150 mg and higher in the single‐dose study. The mean intragastric pH and the percentage of time at pH > 4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose‐effect relationship. Neither serious nor dose‐limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose‐dependent increases in intragastric pH. The acid‐suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid‐related diseases.

Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance.

This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty‐four subjects received the following medication during the following three study periods: 1 mg of i.v. midazolam alone (control phase), 1 mg of i.v. midazolam after 4 days of pretreatment with 400 mg of ketoconazole once daily (CYP3A‐inhibited phase), and 2.5 mg of i.v. midazolam after 10 days of pretreatment with 600 mg of rifampicin once daily (CYP3A‐induced phase). During each study period, 24 h before and after the administration of midazolam, urine samples were collected at 12‐h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam.

Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection. Udenafil is newly developed as a PDE-5 inhibitor. WHAT THIS STUDY ADDS This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects. Udenafil was safe and well tolerated in healthy Korean subjects. The AUC and C(max) of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations. AIM To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor. METHODS A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events. RESULTS Udenafil reached peak plasma concentrations at 0.8-1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3-12.1 h in the single-dose study. The area under the time-concentration curves (AUC) and maximum plasma concentrations (C(max)) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred. CONCLUSIONS Udenafil was safe and well tolerated in healthy volunteers. The AUC and C(max) of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.