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Frequency of CYP2C19 variant alleles in Koreans
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S27eS107
10 mg dose of dexamethasone 30 minutes before starting FOLFOX chemotherapy (folic acid, 5efluorouracil, and oxaliplatin) as anti-emetic preparation. Rhodes index of nausea, vomiting, and retching (RINVR) were measured at 1, 6 hour, Day 1, Day 2, and Day 7 after the administration of ramosetron as a clinical parameter of CINV. Higher score in RINVR was considered as more severe experiences. The genetic polymorphisms of ABCB1 (rs1045642), CYP2D6 (CYP2D6*2 (rs16947), CYP2D6*4 (rs3892097) and CYP2D6*10 (rs1065852)), and HTR3B (rs3758987, rs45460698, and rs1176744) were analyzed from genomic DNA. Results: There was a dosedependent decrease in the nausea and vomiting scores at Day 1 and Day 2, not statistically significant. The RINVR score at Day 1 in participants with HTR3B -100_-102delAAG deletion variants (rs45460698) was significantly higher than wild type participants, regardless of dosages (p ¼ 0.022, the mean ± SD, 0.94 ± 1.60; n ¼ 17 vs. 0.15 ± 0.62; n ¼ 33, respectively). However, the polymorphisms including ABCB1, CYP2D6, and other HTR3B genes did not affect response of ramosetron after chemotherapy. Conclusion: These results suggests that the -AAG deletion variant of the 5HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. The patients carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A07000112311450100). P211 EFFECTS OF GENETIC POLYMORPHISMS OF MULTI DRUG RESISTANCE PROTEIN (MDR1) ON LANSOPRAZOLE METABOLISM IN PEDIATRIC PATIENTS Ragip O. Karaca 1, Said Kalkisim 1, Ersin Gumus 2, Mustafa T. Goktas 3, Aysel Yuce 2, Umit Yasar 1, Atilla Bozkurt 1, Melih O. Babaoglu 1. 1 Hacettepe University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey; 2 Hacettepe University, Faculty of Medicine, Department of Pediatrics, Ankara, Turkey; 3 Yildirim Beyazit University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey Multidrug resistance protein 1 (MDR1, ABCB1, p-glycoprotein) is a drug transporter responsible for drug export in many tissues. Various drugs such as antineoplastics, antiarrhythmics, HIV protease inhibitors, antidepressants, and proton pump inhibitors are substrates of MDR1. Genetic polymorphisms of MDR1 may alter pharmacokinetics of its substrates. Among many genetic variants, 3435C>T, 2677G>T/A AND 1236C>T substitutions have been shown to be clinically important. The aim of this study was to investigate the effects of genetic polymorphisms of MDR1 on lansoprazole metabolism in pediatric patients. A total of 93 children with gastritis (50.5%), gastro-esophageal reflux disease (31.6%), dyspepsia (15.8%) or hematemesis (2.1%) were recruited. A single dose of lansoprazole was administered orally after an overnight fasting for phenotyping. If body weight of the subject was less than 30 kg, a 15 mg lansoprazole was administered and if more than 30 kg, 30 mg was administered. Peripheral venous blood samples were drawn at the third hour to measure plasma concentrations of lansoprazole and 5-hydroxy lansoprazole. Genotyping was performed by using PCR-RFLP. Plasma lansoprazole (L) and 5-hydroxy lansoprazole (L-OH) concentrations were determined by using an HPLC method. L/L-OH metabolic ratios were calculated and compared among genotype groups. The median L/L-OH metabolic ratio (MR) in subjects with the 3435CC genotype (7.02, n¼26) was significantly higher than those with the 3435CT or TT genotypes (4.55, n¼67) (p¼0.009). The median ‘MR’s were 7.02 (n¼21) and 4.67 (n¼72) in the 2677GG genotype group and in the rest of the subjects, respectively (p¼0.048). The ratios for the 1236CC (6.53, n¼23) and 1236CT or TT (4.71, n¼70) genotype groups were not statistically different (p¼0.12). When haplotypes were analyzed, the median MR in the all-wild type (CC-GG-CC) haplotype group (7.17, n¼15) was similar to that in variant allele carriers (6.96, n¼12, p¼0.42). The median plasma lansoprazole concentrations in MDR1 3435CC, 3435CT-TT, 2677GG, 2677GT-TT-GA-TA, 1236CC and 1236CT-TT genotype groups were similar and 214.2 ng/ml, 216.0 ng/ml, 242.7 ng/ml, 203.1 ng/ml, 201.6 ng/ml and 223.4 ng/ml, respectively (p>0.05). The median plasma L-OH concentrations in MDR1 3435CC, 3435CT-TT, 2677GG, 2677GT-TT-GA-TA, 1236CC and 1236CTTT genotype groups were similar and 37.52 ng/ml, 40.88 ng/ml, 33.56 ng/
S87
ml, 40.88 ng/ml, 33.56 ng/ml and 41.88 ng/ml, respectively (p>0.05). In conclusion MDR1 3435C>T AND 2677G>T/A genetic polymorphisms significantly altered the metabolic ratio of lansoprazole/5-hydroxy lansoprazole in pediatric patients with acid-peptic diseases, while 1236C>T variant not significantly affecting this parameter. This project was supported by the Hacettepe University Scientific Research Projects Coordination Unit (09.d06.101.005). P212 EFFECTS OF MDR1 GENETIC POLYMORPHISMS ON INTRASUBJECT VARIABILITIES OF LEVOSULPIRIDE Yong-Bok Lee 1, Hwa Yoon 1, Hea-Young Cho 2. 1 Department of Pharmaceutics, College of Pharmacy, Chonnam National University, Gwangju, South Korea; 2 Department of Pharmaceutics, College of Pharmacy, CHA University, Seongnam, South Korea Levosulpiride, the L-isomer of sulpiride, whose pharmacokinetics displays large interindividual variations, is mainly used in the treatment of psychoses and gastro-intestinal disorders. The purposes of this study were to investigate the homogeneity of variance (homoscedasticity) of levosulpiride pharmacokinetic parameters in ten different studies and to evaluate the relationship between the genetic polymorphisms in MDRl gene and intra-subject variability of levosulpiride. Reference serum data from five healthy male subjects who participated in ten different bioequivalence studies of levosulpiride 25 mg were included in this study. Blood samples were collected at timed intervals for up to 36 hr after drug administration and serum concentrations of levosulpiride were determined by HPLC. Five subjects were genotyped for MDRl (G2677T/A and C3435T) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Pharmacokinetic parameters of levosulpiride were calculated by a model-independent method using WinNonlin. The intrasubject variability is estimated as CV (%) of the parameters. The homogeneity of variance and the relationship between the genotype and intrasubject variability were assessed using SPSS. It was revealed that there were no differences between the variances of the ten studies except for Tmax, AUC0-3hr and AUC0-4hr. The genetic polymorphisms in MDRI were not associated with statistically any significant differences in the intrasubject variability. P213 FREQUENCY OF CYP2C19 VARIANT ALLELES IN KOREANS Seong-Kuk Hong, Min-Je Choi, Jung-Woo Bae. Keimyung University, Daegu, South Korea CYP2C19 enzyme metabolizes numerous clinically important drugs. Genetic polymorphisms in the CYP2C19 gene have been extensively studied and have been shown to contribute to alterations in enzyme activity. The CYP2C19*2 and CYP2C19*3 null alleles and the CYP2C19*17 gain of function allele are the most common CYP2C19 alleles. The CYP2C19*10 and CYP2C19*22 encodes a protein with decreased enzyme activity. The CYP2C19*10 is located 1 bp upstream of the null CYP2C19*2. PCR-RFLP with SmaI and TaqMan genotyping for detection of CYP2C19*2 is not able to distinguish this allele from CYP2C19*10. The aim of this study is to investigate the frequency of CYP2C19 variant alleles in a Korean population. The CYP2C19 gene was genotyped in 397 Korean subjects. CYP2C19 alleles (CYP2C19*1, *2, *3, *10, *17 and *22 alleles) were measured using pyrosequencing genotype method. The frequencies of CYP2C19*1, *2, *3, and *17 allele were 0.646, 0.262, 0.078, and 0.014, respectively. The frequencies of the CYP2C19*1/*1, *1/*2, *1/*3, *1/*17, *2/*17, *2/*2, *2/*3 and *3/*3 genotypes were 0.416, 0.350, 0.093, 0.018, 0.008, 0.063, 0.040 and 0.010, respectively. No CYP2C19*10 and CYP2C19*22 allele were found in the Korean samples. P214 GENETIC FINDING AND FUNCTIONAL CHARACTERIZATION OF CYTOCHROME P450 4F11 GENETIC POLYMORPHISMS IN A KOREAN POPULATION Myeongjin Yi 1, Sung Eun Yoo 1, Sun-Ah Cho 1, Dong-Hyun Kim 1, Jae-Gook Shin 1, 2, Su-Jun Lee 1. 1 Department of Pharmacology and PharmacoGenomics
10 mg dose of dexamethasone 30 minutes before starting FOLFOX chemotherapy (folic acid, 5efluorouracil, and oxaliplatin) as anti-emetic preparation. Rhodes index of nausea, vomiting, and retching (RINVR) were measured at 1, 6 hour, Day 1, Day 2, and Day 7 after the administration of ramosetron as a clinical parameter of CINV. Higher score in RINVR was considered as more severe experiences. The genetic polymorphisms of ABCB1 (rs1045642), CYP2D6 (CYP2D6*2 (rs16947), CYP2D6*4 (rs3892097) and CYP2D6*10 (rs1065852)), and HTR3B (rs3758987, rs45460698, and rs1176744) were analyzed from genomic DNA. Results: There was a dosedependent decrease in the nausea and vomiting scores at Day 1 and Day 2, not statistically significant. The RINVR score at Day 1 in participants with HTR3B -100_-102delAAG deletion variants (rs45460698) was significantly higher than wild type participants, regardless of dosages (p ¼ 0.022, the mean ± SD, 0.94 ± 1.60; n ¼ 17 vs. 0.15 ± 0.62; n ¼ 33, respectively). However, the polymorphisms including ABCB1, CYP2D6, and other HTR3B genes did not affect response of ramosetron after chemotherapy. Conclusion: These results suggests that the -AAG deletion variant of the 5HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. The patients carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A07000112311450100). P211 EFFECTS OF GENETIC POLYMORPHISMS OF MULTI DRUG RESISTANCE PROTEIN (MDR1) ON LANSOPRAZOLE METABOLISM IN PEDIATRIC PATIENTS Ragip O. Karaca 1, Said Kalkisim 1, Ersin Gumus 2, Mustafa T. Goktas 3, Aysel Yuce 2, Umit Yasar 1, Atilla Bozkurt 1, Melih O. Babaoglu 1. 1 Hacettepe University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey; 2 Hacettepe University, Faculty of Medicine, Department of Pediatrics, Ankara, Turkey; 3 Yildirim Beyazit University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey Multidrug resistance protein 1 (MDR1, ABCB1, p-glycoprotein) is a drug transporter responsible for drug export in many tissues. Various drugs such as antineoplastics, antiarrhythmics, HIV protease inhibitors, antidepressants, and proton pump inhibitors are substrates of MDR1. Genetic polymorphisms of MDR1 may alter pharmacokinetics of its substrates. Among many genetic variants, 3435C>T, 2677G>T/A AND 1236C>T substitutions have been shown to be clinically important. The aim of this study was to investigate the effects of genetic polymorphisms of MDR1 on lansoprazole metabolism in pediatric patients. A total of 93 children with gastritis (50.5%), gastro-esophageal reflux disease (31.6%), dyspepsia (15.8%) or hematemesis (2.1%) were recruited. A single dose of lansoprazole was administered orally after an overnight fasting for phenotyping. If body weight of the subject was less than 30 kg, a 15 mg lansoprazole was administered and if more than 30 kg, 30 mg was administered. Peripheral venous blood samples were drawn at the third hour to measure plasma concentrations of lansoprazole and 5-hydroxy lansoprazole. Genotyping was performed by using PCR-RFLP. Plasma lansoprazole (L) and 5-hydroxy lansoprazole (L-OH) concentrations were determined by using an HPLC method. L/L-OH metabolic ratios were calculated and compared among genotype groups. The median L/L-OH metabolic ratio (MR) in subjects with the 3435CC genotype (7.02, n¼26) was significantly higher than those with the 3435CT or TT genotypes (4.55, n¼67) (p¼0.009). The median ‘MR’s were 7.02 (n¼21) and 4.67 (n¼72) in the 2677GG genotype group and in the rest of the subjects, respectively (p¼0.048). The ratios for the 1236CC (6.53, n¼23) and 1236CT or TT (4.71, n¼70) genotype groups were not statistically different (p¼0.12). When haplotypes were analyzed, the median MR in the all-wild type (CC-GG-CC) haplotype group (7.17, n¼15) was similar to that in variant allele carriers (6.96, n¼12, p¼0.42). The median plasma lansoprazole concentrations in MDR1 3435CC, 3435CT-TT, 2677GG, 2677GT-TT-GA-TA, 1236CC and 1236CT-TT genotype groups were similar and 214.2 ng/ml, 216.0 ng/ml, 242.7 ng/ml, 203.1 ng/ml, 201.6 ng/ml and 223.4 ng/ml, respectively (p>0.05). The median plasma L-OH concentrations in MDR1 3435CC, 3435CT-TT, 2677GG, 2677GT-TT-GA-TA, 1236CC and 1236CTTT genotype groups were similar and 37.52 ng/ml, 40.88 ng/ml, 33.56 ng/
S87
ml, 40.88 ng/ml, 33.56 ng/ml and 41.88 ng/ml, respectively (p>0.05). In conclusion MDR1 3435C>T AND 2677G>T/A genetic polymorphisms significantly altered the metabolic ratio of lansoprazole/5-hydroxy lansoprazole in pediatric patients with acid-peptic diseases, while 1236C>T variant not significantly affecting this parameter. This project was supported by the Hacettepe University Scientific Research Projects Coordination Unit (09.d06.101.005). P212 EFFECTS OF MDR1 GENETIC POLYMORPHISMS ON INTRASUBJECT VARIABILITIES OF LEVOSULPIRIDE Yong-Bok Lee 1, Hwa Yoon 1, Hea-Young Cho 2. 1 Department of Pharmaceutics, College of Pharmacy, Chonnam National University, Gwangju, South Korea; 2 Department of Pharmaceutics, College of Pharmacy, CHA University, Seongnam, South Korea Levosulpiride, the L-isomer of sulpiride, whose pharmacokinetics displays large interindividual variations, is mainly used in the treatment of psychoses and gastro-intestinal disorders. The purposes of this study were to investigate the homogeneity of variance (homoscedasticity) of levosulpiride pharmacokinetic parameters in ten different studies and to evaluate the relationship between the genetic polymorphisms in MDRl gene and intra-subject variability of levosulpiride. Reference serum data from five healthy male subjects who participated in ten different bioequivalence studies of levosulpiride 25 mg were included in this study. Blood samples were collected at timed intervals for up to 36 hr after drug administration and serum concentrations of levosulpiride were determined by HPLC. Five subjects were genotyped for MDRl (G2677T/A and C3435T) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Pharmacokinetic parameters of levosulpiride were calculated by a model-independent method using WinNonlin. The intrasubject variability is estimated as CV (%) of the parameters. The homogeneity of variance and the relationship between the genotype and intrasubject variability were assessed using SPSS. It was revealed that there were no differences between the variances of the ten studies except for Tmax, AUC0-3hr and AUC0-4hr. The genetic polymorphisms in MDRI were not associated with statistically any significant differences in the intrasubject variability. P213 FREQUENCY OF CYP2C19 VARIANT ALLELES IN KOREANS Seong-Kuk Hong, Min-Je Choi, Jung-Woo Bae. Keimyung University, Daegu, South Korea CYP2C19 enzyme metabolizes numerous clinically important drugs. Genetic polymorphisms in the CYP2C19 gene have been extensively studied and have been shown to contribute to alterations in enzyme activity. The CYP2C19*2 and CYP2C19*3 null alleles and the CYP2C19*17 gain of function allele are the most common CYP2C19 alleles. The CYP2C19*10 and CYP2C19*22 encodes a protein with decreased enzyme activity. The CYP2C19*10 is located 1 bp upstream of the null CYP2C19*2. PCR-RFLP with SmaI and TaqMan genotyping for detection of CYP2C19*2 is not able to distinguish this allele from CYP2C19*10. The aim of this study is to investigate the frequency of CYP2C19 variant alleles in a Korean population. The CYP2C19 gene was genotyped in 397 Korean subjects. CYP2C19 alleles (CYP2C19*1, *2, *3, *10, *17 and *22 alleles) were measured using pyrosequencing genotype method. The frequencies of CYP2C19*1, *2, *3, and *17 allele were 0.646, 0.262, 0.078, and 0.014, respectively. The frequencies of the CYP2C19*1/*1, *1/*2, *1/*3, *1/*17, *2/*17, *2/*2, *2/*3 and *3/*3 genotypes were 0.416, 0.350, 0.093, 0.018, 0.008, 0.063, 0.040 and 0.010, respectively. No CYP2C19*10 and CYP2C19*22 allele were found in the Korean samples. P214 GENETIC FINDING AND FUNCTIONAL CHARACTERIZATION OF CYTOCHROME P450 4F11 GENETIC POLYMORPHISMS IN A KOREAN POPULATION Myeongjin Yi 1, Sung Eun Yoo 1, Sun-Ah Cho 1, Dong-Hyun Kim 1, Jae-Gook Shin 1, 2, Su-Jun Lee 1. 1 Department of Pharmacology and PharmacoGenomics