Nifedipine Pharmacokinetics Are Influenced by CYP3A5 Genotype When Used as a Preterm Labor Tocolytic

David M. Haas; Sara K. Quinney; Jayanti M. Clay; Jamie L. Renbarger; Mary F. Hebert; Shannon Clark; Jason G. Umans; Steve N. Caritis; for the Obstetric-Fetal Pharmacology Research Units Network

doi:10.1055/s-0032-1323590

American Journal of Perinatology, Table of Contents

Am J Perinatol 2013; 30(04): 275-282
DOI: 10.1055/s-0032-1323590

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nifedipine Pharmacokinetics Are Influenced by CYP3A5 Genotype When Used as a Preterm Labor Tocolytic

Authors

David M. Haas

¹Department of Obstetrics and Gynecology Indiana University School of Medicine, Indianapolis
Sara K. Quinney

¹Department of Obstetrics and Gynecology Indiana University School of Medicine, Indianapolis
Jayanti M. Clay

¹Department of Obstetrics and Gynecology Indiana University School of Medicine, Indianapolis
Jamie L. Renbarger

²Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis
Mary F. Hebert

³Departments of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, Washington
Shannon Clark

⁴Division of MFM, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
Jason G. Umans

⁵Center for Clinical and Translational Science, Georgetown-Howard Universities, Washington, District of Columbia

⁶Medstar Health Research Institute, Hyattsville, Maryland
Steve N. Caritis

⁷Division of MFM, Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

for the Obstetric-Fetal Pharmacology Research Units Network

Abstract

Objective To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy.

Study Design Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5 and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma, and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7).

Results Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68 ± 1.56 hours. The area under the curve from 0 to 6 hours for the women receiving nifedipine every 6 hours was 207 ± 138 µg·h /L. Oral clearance was different between high expressers and low expressers (232.0 ± 37.8 µg/mL versus 85.6 ± 45.0 µg/mL, respectively; p = 0.007).

Conclusion CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women.

Keywords

nifedipine - pharmacokinetics - pharmacogenetics - pregnancy - tocolysis

Full Text

References

References
1 King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003; (1) CD002255
2 Grimes DA, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006; 108: 986-989
3 Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113: 585-594
4 Goldenberg RL. The management of preterm labor. Obstet Gynecol 2002; 100 (5 Pt 1) 1020-1037
5 Hearne AE, Nagey DA. Therapeutic agents in preterm labor: tocolytic agents. Clin Obstet Gynecol 2000; 43: 787-801
6 Ferguson II JE, Schutz T, Pershe R, Stevenson DK, Blaschke T. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 1989; 161 (6 Pt 1) 1485-1490
7 Papatsonis DNM, Bos JM, van Geijn HP, Lok CAR, Dekker GA. Nifedipine pharmacokinetics and plasma levels in the management of preterm labor. Am J Ther 2007; 14: 346-350
8 Haas DM, Quinney SK, McCormick CL, Jones DR, Renbarger JL. A pilot study of the impact of genotype on nifedipine pharmacokinetics when used as a tocolytic. J Matern Fetal Neonatal Med 2011; 25: 419-423
9 Andersson T, Flockhart DA, Goldstein DB , et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005; 78: 559-581
10 Swen JJ, Huizinga TW, Gelderblom H , et al. Translating pharmacogenomics: challenges on the road to the clinic. PLoS Med 2007; 4: e209
11 Patki KC, Von Moltke LL, Greenblatt DJ. In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of CYP3a4 and CYP3a5 . Drug Metab Dispos 2003; 31: 938-944
12 Kim RB, Wandel C, Leake B , et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408-414
13 Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992; 13: 434-439
14 Lee S-J, Bell DA, Coulter SJ, Ghanayem B, Goldstein JA. Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype. J Pharmacol Exp Ther 2005; 313: 302-309
15 Lee S-J, Usmani KA, Chanas B , et al. Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics 2003; 13: 461-472
16 Fukuda T, Onishi S, Fukuen S , et al. CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers. Pharmacogenomics J 2004; 4: 34-39
17 Egbelakin A, Ferguson MJ, MacGill EA , et al. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2011; 56: 361-367
18 The R-project for statistical computing; 2009. Available at: http://www.R-project.org . Accessed July 8, 2010
19 Andrew MA, Easterling TR, Carr DB , et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies. Clin Pharmacol Ther 2007; 81: 547-556
20 Buchanan ML, Easterling TR, Carr DB , et al. Clonidine pharmacokinetics in pregnancy. Drug Metab Dispos 2009; 37: 702-705
21 Eyal S, Easterling TR, Carr D , et al. Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos 2010; 38: 833-840
22 Hebert MF, Ma X, Naraharisetti SB , et al; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009; 85: 607-614
23 Barton JR, Prevost RR, Wilson DA, Whybrew WD, Sibai BM. Nifedipine pharmacokinetics and pharmacodynamics during the immediate postpartum period in patients with preeclampsia. Am J Obstet Gynecol 1991; 165 (4 Pt 1) 951-954
24 Prevost RR, Akl SA, Whybrew WD, Sibai BM. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy 1992; 12: 174-177
25 Sorkin EM, Clissold SP, Brogden RN. Nifedipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs 1985; 30: 182-274
26 Taburet AM, Singlas E, Colin JN, Banzet O, Thibonnier M, Corvol P. Pharmacokinetic studies of nifedipine tablet. Correlation with antihypertensive effects. Hypertension 1983; 5 (4 Pt 2) II29-II33
27 Product Information. Procardia(R), nifedipine capsules. Clearwater, FL: Pfizer labs; 2000
28 Balogh A, Gessinger S, Svarovsky U , et al. Can oral contraceptive steroids influence the elimination of nifedipine and its primary pryidine metabolite in humans?. Eur J Clin Pharmacol 1998; 54: 729-734
29 Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 2004; 5: 243-272
30 Williams JA, Ring BJ, Cantrell VE , et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7 . Drug Metab Dispos 2002; 30: 883-891
31 Kuehl P, Zhang J, Lin Y , et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27: 383-391
32 Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 . J Natl Cancer Inst 1998; 90: 1225-1229
33 Amirimani B, Ning B, Deitz AC, Weber BL, Kadlubar FF, Rebbeck TR. Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen 2003; 42: 299-305
34 Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ, Wilkinson GR. CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5′-promoter region polymorphism. Clin Pharmacol Ther 2000; 68: 82-91
35 Spurdle AB, Goodwin B, Hodgson E , et al. The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 2002; 12: 355-366
36 Stamer UM, Lee EH, Rauers NI , et al. CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care. Anesth Analg 2011; 113: 48-54
37 Wojnowski L, Hustert E, Klein K , et al. Re: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 . J Natl Cancer Inst 2002; 94: 630-631 ; author reply 631–632
38 Miao J, Jin Y, Marunde RL , et al. Association of genotypes of the CYP3A cluster with midazolam disposition in vivo. Pharmacogenomics J 2009; 9: 319-326
39 Quinney SK, Miao J, Jin Y , et al. CYP3A gene cluster analysis and midazolam pharmacokinetics. Clin Pharmacol Ther 2009; 85 (S1) PI-54
40 Manninen AK, Juhakoski A. Nifedipine concentrations in maternal and umbilical serum, amniotic fluid, breast milk and urine of mothers and offspring. Int J Clin Pharmacol Res 1991; 11: 231-236
41 Pirhonen JP, Erkkola RU, Ekblad UU, Nyman L. Single dose of nifedipine in normotensive pregnancy: nifedipine concentrations, hemodynamic responses, and uterine and fetal flow velocity waveforms. Obstet Gynecol 1990; 76 (5 Pt 1) 807-811
42 Atkinson DE, Brice-Bennett S, D'Souza SW. Antiepileptic medication during pregnancy: does fetal genotype affect outcome?. Pediatr Res 2007; 62: 120-127
43 ACOG Committee on Practice Bulletins. American College of Obstetricians and Gynecologist. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologist. Number 43, May 2003. Management of preterm labor. Obstet Gynecol 2003; 101 (5 Pt 1) 1039-1047
44 Scott SA, Sangkuhl K, Gardner EE , et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011; 90: 328-332
45 Asseburg C, Frank M, Köhne CH , et al. Cost-effectiveness of targeted therapy with cetuximab in patients with K-ras wild-type colorectal cancer presenting with initially unresectable metastases limited to the liver in a German setting. Clin Ther 2011; 33: 482-497
46 Ibrahim EM, Zekri JM, Bin Sadiq BM. Cetuximab-based therapy for metastatic colorectal cancer: a meta-analysis of the effect of K-ras mutations. Int J Colorectal Dis 2010; 25: 713-721