Abstract
This study aimed at investigating the contribution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacokinetics and pharmacodynamics in Black Africans from Benin. Fifty-one healthy volunteers were genotyped for VKORC1 1173C>T polymorphism. All of the subjects had previously been genotyped for CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*9 and CYP2C9*11 alleles. Thirty-six subjects were phenotyped with a single 8 mg oral dose of acenocoumarol by measuring plasma concentrations of (R)- and (S)-acenocoumarol 8 and 24 h after the administration using chiral liquid-chromatography tandem mass-spectrometry. International normalized ratio (INR) values were determined prior to and 24 h after the drug intake. The allele frequency of VKORC1 variant (1173C>T) was 1.96% (95% CI 0.0–4.65%). The INR values did not show statistically significant difference between the CYP2C9 genotypes, but were correlated with body mass index and age at 24 h post-dosing (P < 0.05). At 8 h post dose, the (S)-acenocoumarol concentrations in the CYP2C9*5/*8 and CYP2C9*9/*11 genotypes were about 1.9 and 5.1 fold higher compared with the CYP2C9*1/*1 genotype and 2.2- and 6.0-fold higher compared with the CYP2C9*1/*9 group, respectively. The results indicated that pharmacodynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associated with CYP2C9*5/*8 and *9/*11 variant and demographic factors (age and weight) in Beninese subjects. Significant association between plasma (S)-acenocoumarol concentration and CYP2C9 genotypes suggested the use of (S)-acenocoumarol for the phenotyping purpose. Larger number of subjects is needed to study the effect of VKORC1 1173C>T variant due to its low frequency in Beninese population.
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References
Allabi AC, Gala JL, Desager JP, Heusterspreute M, Horsmans Y (2003) Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 56:653–657
Allabi AC, Gala JL, Horsmans Y, Babaoglu MO, Bozkurt A, Heusterspreute M, Yasar U (2004) Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. Clin Pharmacol Ther 76:113–118
Allabi AC, Gala JL, Horsmans Y (2005) CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population. Pharmacogenet Genomics 15:779–786
Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D, Gaston KL, Waddell CD, Chirico MJ, Johnson JA (2006) Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 79:291–302
Belle DJ, Singh H (2008) Genetic factors in drug metabolism. Am Fam Physician 77:1553–1560
Blaisdell J, Jorge-Nebert LF, Coulter S, Ferguson SS, Lee SJ, Chanas B, Xi T, Mohrenweiser H, Ghanayem B, Goldstein JA (2004) Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 14:527–537
Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, Loriot MA (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106:135–140
Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA, Viana MA, Patel SR, Johnson JA (2010) Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 87:459–464
D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649
Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJ, Stein CM, Wilkinson GR, Schwarz UI (2001) Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 60:382–387
Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 84:326–331
Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, Muller CR, Wienker TF, Oldenburg J (2005) VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 94:773–779
Hillman MA, Wilke RA, Caldwell MD, Berg RL, Glurich I, Burmester JK (2004) Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 14:539–547
Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P, Daly AK, Wynne H (2004) Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 75:204–212
Li T, Lange LA, Li X, Susswein L, Bryant B, Malone R, Lange EM, Huang TY, Stafford DW, Evans JP (2006) Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 43:740–744
Markatos CN, Grouzi E, Politou M, Gialeraki A, Merkouri E, Panagou I, Spiliotopoulou I, Travlou A (2008) VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients. Pharmacogenomics 9:1631–1638
Meinertz T, Kasper W, Kahl C, Jahnchen E (1978) Anticoagulant activity of the enantiomers of acenocoumarol. Br J Clin Pharmacol 5:187–188
Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I, Hermida J (2006) The c.-1639G>A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol 133:183–187
Morin S, Bodin L, Loriot MA, Thijssen HH, Robert A, Strabach S, Verstuyft C, Tregouet DA, Dubert L, Laurent-Puig P, Funck-Brentano C, Jaillon P, Beaune PH, Becquemont L (2004) Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther 75:403–414
Rettie AE, Farin FM, Beri NG, Srinouanprachanh SL, Rieder MJ, Thijssen HH (2006) A case study of acenocoumarol sensitivity and genotype–phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9. Br J Clin Pharmacol 62:617–620
Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293
Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541
Schalekamp T, Brasse BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A (2006) VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 80:13–22
Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333
Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52:447–450
Spreafico M, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F, Mannucci PM, Peyvandi F (2008) Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics 9:1237–1250
Sychev DA, Ignat’ev IV, Kropacheva ES, Emel’ianov NV, Milovanova VV, Naumova Iu A, Kosovskaia AV, Dobrovol’skii OB, Tashenova AI, Panchenko EP, Kukes VG (2011) CYP2C9 and VKORC1 gene polymorphism and acenocoumarol anticoagulant activity in Russian patients at high risk of thromboembolic complications. Vestn Ross Akad Med Nauk 3:7–10
Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, Pengo V, Barban M, Padrini R, Ieiri I, Otsubo K, Kashima T, Kimura S, Kijima S, Echizen H (2006) Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 16:101–110
Teichert M, van Noord C, Uitterlinden AG, Hofman A, Buhre PN, De Smet PA, Straus S, Stricker BH, Visser LE (2011) Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Haematol 153:379–385
Thijssen HH, Ritzen B (2003) Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther 74:61–68
Thijssen HH, Flinois JP, Beaune PH (2000) Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 28:1284–1290
Thijssen HH, Drittij MJ, Vervoort LM, de Vries-Hanje JC (2001) Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 70:292–298
Ufer M (2005) Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 44:1227–1246
Van Geest-Daalderop JH, Hutten BA, Pequeriaux NC, Levi M, Sturk A (2009) Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model. J Thromb Thrombolysis 27:207–214
van Leeuwen Y, Rosendaal FR, van der Meer FJ (2008) The relationship between maintenance dosages of three vitamin K antagonists: acenocoumarol, warfarin and phenprocoumon. Thromb Res 123:225–230
van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, Verhoef TI, van Meegen E, Rosendaal FR, Maitland-van der Zee AH (2011) Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J (Epub ahead of print)
Xie HG, Prasad HC, Kim RB, Stein CM (2002) CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 54:1257–1270
Yasar U, Aklillu E, Canaparo R, Sandberg M, Sayi J, Roh HK, Wennerholm A (2002) Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations. Eur J Clin Pharmacol 58:555–558
Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751
Acknowledgments
The authors would like to thank the staff of the Hospital (Hôpital de Zone de COVE) for their technical assistance. We also wish to thank Angelbert Agbokponto for his help in the clinical part of the study; Veronique Schlumder for her technical assistance for genotyping; and Dr Paul Aliu to review internally this article.
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The authors have no conflict of interest regarding this work.
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Allabi, A.C., Horsmans, Y., Alvarez, JC. et al. Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects. Eur J Drug Metab Pharmacokinet 37, 125–132 (2012). https://doi.org/10.1007/s13318-011-0056-7
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DOI: https://doi.org/10.1007/s13318-011-0056-7