CYP2D6 PHENOTYPES AMONG JAVANESE AND SUNDANESE SUBJECTS IN INDONESIA
DOI:
https://doi.org/10.22159/ijap.2019.v11s5.T0038Keywords:
CYP2D6, Javanese and Sundanese, Indonesia, Metoprolol, PhenotypeAbstract
Objective: The objective of this study was to determine CYP2D6 phenotype in a Javanese and Sundanese healthy subject in Indonesia.
Methods: Ninety unrelated healthy Indonesian subjects from Java and Sunda were studied. Metoprolol was used as phenotyping substrate. A 100 mg
oral tablet of metoprolol was administered to all the subjects. Urinary metoprolol and α-hydroxymetoprolol were determined to calculate metoprolol
metabolic ratio (MR). Determination of metoprolol and α-hydroxymetoprolol was carried out by high performance liquid chromatography method.
Results: Metoprolol MR varied widely (from 0.08 to 72.75). One subject (1.11%) in the study was classified as poor metabolizer (PM), one subject
(1.11%) as ultrarapid metabolizer, and the remaining 88 subjects (97.78%) were classified as extensive metabolizers.
Conclusion: The frequencies of PM for the CYP2D6 phenotype (1.11%) in the Javanese and Sundanese population are in concordance with most
results of oxidation metabolizers in other Asian populations.
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References
1. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome
P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and
functional diversity. Pharmacogenomics J 2005;5:6-13.
2. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP.
Interindividual variations in human liver cytochrome P-450 enzymes
involved in the oxidation of drugs, carcinogens and toxic chemicals:
Studies with liver microsomes of 30 Japanese and 30 caucasians.
J Pharmacol Exp Ther 1994;270:414-23.
3. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6:
Overview and update on pharmacology, genetics, biochemistry. Naunyn
Schmiedebergs Arch Pharmacol 2004;369:23-37.
4. Ozdemir M, Crewe KH, Tucker GT, Rostami-Hodjegan A. Assessment
of in vivo CYP2D6 activity: Differential sensitivity of commonly used
probes to urine pH. J Clin Pharmacol 2004;44:1398-404.
5. Vittalrao AM, Thanusubramanian H, Kumari KM, Shaik AB.
Pharmacotherapy of heart failure. Asian J Pharm Clin Res 2018;11:78-
87.
6. Venkateswarlu P, Kumar BN, Seshaiah K, Prasad VV. Selective and
sensitive method for the determination of metoprolol in human plasma
using liquid chromatography coupled with tandem mass spectrometry.
Acta Pharm 2010;60:177-84.
7. Fang J, Semple HA, Song J. Determination of metoprolol, and its four
metabolites in dog plasma. J Chromatogr B Analyt Technol Biomed
Life Sci 2004;809:9-14.
8. Vattipally M, Mahesh AK, Kodati D, Yellu NR. Population
pharmacokinetics and clinical response of metoprolol in South Indian
hyperternsive patients. Asian J Pharm Clin Res 2014;7:140-3.
9. Li Q, Wang R. Simultaneous analysis of tramadol, metoprolol and their
metabolites in human plasma and urine by high performance liquid
chromatography. Chin Med J (Engl) 2006;119:2013-7.
10. Meyer UA, Zanger UM. Molecular mechanisms of genetic
polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol
1997;37:269-96.
11. Masimirembwa C, Hasler J, Bertilssons L, Johansson I, Ekberg O,
Ingelman-Sundberg M. Phenotype and genotype analysis of debrisoquine
hydroxylase (CYP2D6) in a black Zimbabwean population. Reduced
enzyme activity and evaluation of metabolic correlation of CYP2D6
probe drugs. Eur J Clin Pharmacol 1996;51:117-22.
12. Basci NE, Bozkurt A, Isimer A, Kayaalp SO. Correlation between the
metabolic ratios of debrisoquine and metoprolol in Turkish subjects.
Pharmacol Toxicol 1994;75:62-4.
13. Labbé L, Sirois C, Pilote S, Arseneault M, Robitaille NM, Turgeon J,
et al. Effect of gender, sex hormones, time variables and physiological
urinary pH on apparent CYP2D6 activity as assessed by metabolic
ratios of marker substrates. Pharmacogenetics 2000;10:425-38.
14. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in
drug responses. Pharmacol Res 2007;55:81-95.
15. Ismail R, Hussein A, Teh LK, Nizam Isa M. CYP2D6 phenotypes
among malays in Malaysia. J Clin Pharm Ther 2000;25:379-83.
16. Sohn DR, Shin SG, Park CW, Kusaka M, Chiba K, Ishizaki T,
et al. Metoprolol oxidation polymorphism in a Korean population:
Comparison with native Japanese and Chinese populations. Br J Clin
Pharmacol 1991;32:504-7.
17. McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF.
Metoprolol metabolism and debrisoquine oxidation polymorphism –
population and family studies. Br J Clin Pharmacol 1985;20:555-66.
18. Hadasová E, Franke G, Zschiesche M, Cesková E, Zelenková O,
Siegmund W. Debrisoquine 4-hydroxylation and sulphamethazine
N-acetylation in patients with schizophrenia and major depression. Br J
Clin Pharmacol 1996;41:428-31.
19. Estevez F, Giusti M, Parrillo S, Oxandabarat J. Dextromethorphan
O-demethylation polymorphism in the Uruguayan population. Eur J
Clin Pharmacol 1997;52:417-8.
20. López M, Guerrero J, Jung-Cook H, Alonso ME. CYP2D6 genotype
and phenotype determination in a Mexican Mestizo population. Eur J
Clin Pharmacol 2005;61:749-54.
21. Ebeshi BU, Bolaji OO, Masimirembwa CM. Cytochrome P450 2D6
(CYP2D6) genotype and phenotype determinationin the Nigerian
populations. Asian J Pharm Health Sci 2011;1:47-54.
22. Horai Y, Nakano M, Ishizaki T, Ishikawa K, Zhou HH, Zhou BI, et al.
Metoprolol and mephenytoin oxidation polymorphisms in far Eastern
oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol
Ther 1989;46:198-207.
23. Patramurti C, Sugiyanto S, Nurrochmad A, Martono S. Polymorphism
of cytochrome P450 2A6 (CYP2A6*1 and CYP2A6*4) among
Javanese Indonesian smoker and non smoker. Ind J Pharm 2015;6:11-9.
24. Cai WM, Chen B, Liu YX, Chu X. Dextromethorphan metabolic
phenotyping in a Chinese population. Zhongguo Yao Li Xue Bao
1997;18:441-4.
P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and
functional diversity. Pharmacogenomics J 2005;5:6-13.
2. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP.
Interindividual variations in human liver cytochrome P-450 enzymes
involved in the oxidation of drugs, carcinogens and toxic chemicals:
Studies with liver microsomes of 30 Japanese and 30 caucasians.
J Pharmacol Exp Ther 1994;270:414-23.
3. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6:
Overview and update on pharmacology, genetics, biochemistry. Naunyn
Schmiedebergs Arch Pharmacol 2004;369:23-37.
4. Ozdemir M, Crewe KH, Tucker GT, Rostami-Hodjegan A. Assessment
of in vivo CYP2D6 activity: Differential sensitivity of commonly used
probes to urine pH. J Clin Pharmacol 2004;44:1398-404.
5. Vittalrao AM, Thanusubramanian H, Kumari KM, Shaik AB.
Pharmacotherapy of heart failure. Asian J Pharm Clin Res 2018;11:78-
87.
6. Venkateswarlu P, Kumar BN, Seshaiah K, Prasad VV. Selective and
sensitive method for the determination of metoprolol in human plasma
using liquid chromatography coupled with tandem mass spectrometry.
Acta Pharm 2010;60:177-84.
7. Fang J, Semple HA, Song J. Determination of metoprolol, and its four
metabolites in dog plasma. J Chromatogr B Analyt Technol Biomed
Life Sci 2004;809:9-14.
8. Vattipally M, Mahesh AK, Kodati D, Yellu NR. Population
pharmacokinetics and clinical response of metoprolol in South Indian
hyperternsive patients. Asian J Pharm Clin Res 2014;7:140-3.
9. Li Q, Wang R. Simultaneous analysis of tramadol, metoprolol and their
metabolites in human plasma and urine by high performance liquid
chromatography. Chin Med J (Engl) 2006;119:2013-7.
10. Meyer UA, Zanger UM. Molecular mechanisms of genetic
polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol
1997;37:269-96.
11. Masimirembwa C, Hasler J, Bertilssons L, Johansson I, Ekberg O,
Ingelman-Sundberg M. Phenotype and genotype analysis of debrisoquine
hydroxylase (CYP2D6) in a black Zimbabwean population. Reduced
enzyme activity and evaluation of metabolic correlation of CYP2D6
probe drugs. Eur J Clin Pharmacol 1996;51:117-22.
12. Basci NE, Bozkurt A, Isimer A, Kayaalp SO. Correlation between the
metabolic ratios of debrisoquine and metoprolol in Turkish subjects.
Pharmacol Toxicol 1994;75:62-4.
13. Labbé L, Sirois C, Pilote S, Arseneault M, Robitaille NM, Turgeon J,
et al. Effect of gender, sex hormones, time variables and physiological
urinary pH on apparent CYP2D6 activity as assessed by metabolic
ratios of marker substrates. Pharmacogenetics 2000;10:425-38.
14. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in
drug responses. Pharmacol Res 2007;55:81-95.
15. Ismail R, Hussein A, Teh LK, Nizam Isa M. CYP2D6 phenotypes
among malays in Malaysia. J Clin Pharm Ther 2000;25:379-83.
16. Sohn DR, Shin SG, Park CW, Kusaka M, Chiba K, Ishizaki T,
et al. Metoprolol oxidation polymorphism in a Korean population:
Comparison with native Japanese and Chinese populations. Br J Clin
Pharmacol 1991;32:504-7.
17. McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF.
Metoprolol metabolism and debrisoquine oxidation polymorphism –
population and family studies. Br J Clin Pharmacol 1985;20:555-66.
18. Hadasová E, Franke G, Zschiesche M, Cesková E, Zelenková O,
Siegmund W. Debrisoquine 4-hydroxylation and sulphamethazine
N-acetylation in patients with schizophrenia and major depression. Br J
Clin Pharmacol 1996;41:428-31.
19. Estevez F, Giusti M, Parrillo S, Oxandabarat J. Dextromethorphan
O-demethylation polymorphism in the Uruguayan population. Eur J
Clin Pharmacol 1997;52:417-8.
20. López M, Guerrero J, Jung-Cook H, Alonso ME. CYP2D6 genotype
and phenotype determination in a Mexican Mestizo population. Eur J
Clin Pharmacol 2005;61:749-54.
21. Ebeshi BU, Bolaji OO, Masimirembwa CM. Cytochrome P450 2D6
(CYP2D6) genotype and phenotype determinationin the Nigerian
populations. Asian J Pharm Health Sci 2011;1:47-54.
22. Horai Y, Nakano M, Ishizaki T, Ishikawa K, Zhou HH, Zhou BI, et al.
Metoprolol and mephenytoin oxidation polymorphisms in far Eastern
oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol
Ther 1989;46:198-207.
23. Patramurti C, Sugiyanto S, Nurrochmad A, Martono S. Polymorphism
of cytochrome P450 2A6 (CYP2A6*1 and CYP2A6*4) among
Javanese Indonesian smoker and non smoker. Ind J Pharm 2015;6:11-9.
24. Cai WM, Chen B, Liu YX, Chu X. Dextromethorphan metabolic
phenotyping in a Chinese population. Zhongguo Yao Li Xue Bao
1997;18:441-4.
Published
15-09-2019
How to Cite
UTAMI, P. I., SUGIYANTO, S., MARTONO, S., & HAKIM, L. (2019). CYP2D6 PHENOTYPES AMONG JAVANESE AND SUNDANESE SUBJECTS IN INDONESIA. International Journal of Applied Pharmaceutics, 11(5), 36–39. https://doi.org/10.22159/ijap.2019.v11s5.T0038
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