Hee-Doo Yoo

Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10

BACKGROUND AND PURPOSE The objective of this study was to investigate the combined influence of genetic polymorphisms in ABCB1 and CYP2D6 genes on risperidone pharmacokinetics.

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. * Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. * Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS * A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. * Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. * ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h(-1). The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h(-1). Absorption rate constant was estimated at 0.24 h(-1) and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol.

Influence of CYP3A and CYP2C19 Genetic Polymorphisms on the Pharmacokinetics of Cilostazol in Healthy Subjects

The objective of this study was to investigate the influence of genetic polymorphisms in the CYP3A and CYP2C19 genes on cilostazol pharmacokinetics, with the drug being administered orally as a 50‐mg single dose in healthy subjects. CYP2C19 genotypes in individuals with the CYP3A5*3/*3 genotype were associated with statistically significant differences (P < 0.05) in cilostazol pharmacokinetics parameters (apparent oral clearance (CL/F) and terminal half‐life (t1/2)). This indicates that CYP2C19 polymorphisms play an important role in the metabolism of cilostazol only in individuals with the CYP3A5*3/*3 genotype, which has low metabolic activity.

INFLUENCE OF ABCB1 GENETIC POLYMORPHISMS ON THE PHARMACOKINETICS OF LEVOSULPIRIDE IN HEALTHY SUBJECTS

The purposes of this study were to clarify the involvement of P-glycoprotein in the absorption of levosulpiride in knockout mice that lack the Abcb1a/ 1b gene, and to evaluate the relationship between genetic polymorphisms in ABCB1 (exon 12, 21 and 26) and levosulpiride disposition in healthy subjects. The plasma and brain samples were obtained after oral administration (10 microg/g) of levosulpiride to abcb1a/1b(-/-) and wild-type mice (n=3 approximately 6 at each time point). The average brain-to-plasma concentration ratio and blood-brain barrier partitioning of levosulpiride were 2.3- and 2.0-fold higher in Abcb1a/1b(-/-) mice than in wild-type mice, respectively. A total of 58 healthy Korean volunteers receiving a single oral dose of 25 mg levosulpiride participated in this study. The subjects were evaluated for polymorphisms of the ABCB1 exon 12 C1236T, exon 21 G2677A/T (Ala893Ser/Thr) and exon 26 C3435T using polymerase chain reaction restriction fragment length polymorphism. The PK parameters (AUC(0-4h), AUC(0-infinity) and C(max.)) of ABCB1 2677TT and 3435TT subjects were significantly higher than those of subjects with at least one wild-type allele (P<0.05). The results indicate that levosulpiride is a P-glycoprotein substrate in vivo, which is supported by the effects of SNPs 2677G>A/T in exon 21 and 3435C>T in exon 26 of ABCB1 on levosulpiride disposition.

Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes

Interindividual variability in oral drug efficacy and toxicity is commonly observed in all therapeutic areas. Importantly, interindividual variability in drug uptake and metabolism can result in poor drug response, adverse drug reactions, or unfavorable drug-drug interaction. One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes. Pharmacogenetics are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution. Knowledge of the genotype-phenotype correlation and frequency distribution of functional single nucleotide polymorphisms may be a valuable tool for individualizing drug therapy. This information can also be useful for explaining inter-individual and inter-ethnic variations in drug response and/or adverse effects. In this review, we focus on the interplay between efflux transporter (ATP-binding cassette, sub-family B (MDR/TAP), member 1/ABCB1) and cytochrome P450s according to genetic polymorphism.

Bioequivalence of Cholicerin Soft Capsule to Gliatilin Soft Capsule (Choline Alphoscerate 400 mg)

【The purpose of the present study was to evaluate the bioequivalence of two choline alphoscerate soft capsules, Gliatilin soft capsule (Daewoong Pharmaceuticals Co., Ltd.) and Cholicerin soft capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Serum concentrations of choline after oral administration of choline alphoscerate were determined using a validated LC/MS/MS method. This method showed linear response over the concentration range of 0.5-20

Bioequivalence of Pinatos Capsule 10 mg to Ketas Capsule 10 mg (Ibudilast 10 mg)

{\mu}g

Bioequivalence of Famvir Tablet 750 mg to Famcivir Tablet 750 mg (Famciclovir 750 mg)

/mL with correlation coefficient of 0.9999. The lower limit of quantitation using 100

Bioequivalence of SCD Zaltoprofen Tablet to Soleton ® Tablet (Zaltoprofen 80 mg)

{\mu}L

Development and Validation of an HPLC Method for the Pharmacokinetic Study of Pentoxifylline in Human Serum

of serum was 0.5