Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin

Chih-Hsuan Hsin, Marc S Stoffel, Malaz Gazzaz, Elke Schaeffeler, Matthias Schwab, Uwe Fuhr, Max Taubert, Chih-Hsuan Hsin, Marc S Stoffel, Malaz Gazzaz, Elke Schaeffeler, Matthias Schwab, Uwe Fuhr, Max Taubert

Abstract

Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive. Since SNPs are in incomplete linkage disequilibrium, considering combinations of these SNPs might be necessary to assess the role of polymorphisms in digoxin pharmacokinetics accurately. In this study, the relationship between SNP combinations and digoxin pharmacokinetics was explored via a population pharmacokinetic approach in 40 volunteers who received oral doses of 0.5 mg digoxin. Concerning the SNPs 1236/2677/3435, the following combinations were evaluated: CGC, CGT, and TTT. Carriers of CGC/CGT and TTT/TTT had 35% higher apparent bioavailability compared to the reference group CGC/CGC, while no difference was seen in CGC/TTT carriers. No significant effect on renal clearance was observed. The population pharmacokinetic model supports the use of oral digoxin as a phenotyping substrate of intestinal P-gp, but not to assess renal P-gp activity.

Trial registration: ClinicalTrials.gov NCT02515526 NCT02743260.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Relative difference in (A) apparent bioavailabilities and (B) renal clearance comparing different SNP combination groups to the reference SNP combination CGC/CGC. Median and 95% confidence intervals (95% CI) of fixed effects parameter estimates obtained from a bootstrap. The vertical dashed line represents no difference compared to the reference SNP combination. Refer to Table 3 for further information.
Figure 2
Figure 2
Visual predictive check of the final model (model 4) of (A) plasma, (B) urine. Solid (dashed) lines represent medians (5%, 95% percentiles) of observed concentrations; orange, blue and orange areas represent 95% confidence intervals of 5%, 50% and 95% percentiles predicted by the model. For a correctly specified compartmental model, observed medians should lie inside the middle blue boxes. Observed 95% percentiles should lie within the upper and 5% percentiles within the lower orange boxes.
Figure 3
Figure 3
Goodness-of-fit plots of final model (model 4) of (A) plasma concentrations and (B) urine concentrations.

References

    1. Benet LZ, Bowman CM, Sodhi JK. How transporters have changed basic pharmacokinetic understanding. AAPS J. 2019;21:103.
    1. Yee SW, et al. Influence of transporter polymorphisms on drug disposition and response: A perspective from the International Transporter Consortium. Clin. Pharmacol. Ther. 2018;104:803–817.
    1. Franke R, Gardner E, Sparreboom A. Pharmacogenetics of drug transporters. Curr. Pharm. Des. 2010;16:220–230.
    1. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta Biomembr. 1976;455:152–162.
    1. Cascorbi I. P-glycoprotein: Tissue distribution, substrates, and functional consequences of genetic variations. In: Fromm M, Kim R, editors. Handbook of Experimental Pharmacology. Berlin: Springer; 2011. pp. 261–283.
    1. Han LW, Gao C, Mao Q. An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Expert Opin. Drug Metab. Toxicol. 2018;14:817–829.
    1. Yano K, Seto S, Kamioka H, Mizoi K, Ogihara T. Testosterone and androstenedione are endogenous substrates of P-glycoprotein. Biochem. Biophys. Res. Commun. 2019;520:166–170.
    1. Hodges LM, et al. Very important pharmacogene summary. Pharmacogenet. Genomics. 2011;21:152–161.
    1. Ieiri I. Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) Drug Metab. Pharmacokinet. 2012;27:85–105.
    1. Sakaeda T. MDR1 genotype-related pharmacokinetics: Fact or fiction? Drug Metab. Pharmacokinet. 2005;20:391–414.
    1. Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu. Rev. Pharmacol. Toxicol. 2003;43:285–307.
    1. Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther. Drug Monit. 2004;26:180–185.
    1. Oswald S, Terhaag B, Siegmund W. In vivo probes of drug transport: Commonly used probe drugs to assess function of intestinal P-glycoprotein (ABCB1) in humans. In: Fromm M, Kim R, editors. Handbook of Experimental Pharmacology. Berlin: Springer; 2011. pp. 403–447.
    1. Glaeser H. Importance of P-glycoprotein for drug–drug interactions. In: Fromm M, Kim R, editors. Handbook of Experimental Pharmacology. Berlin: Springer; 2011. pp. 285–297.
    1. U.S. Food and Drug Administration. Clinical drug interaction studies-study design, data analysis, and clinical implications guidance for industry. Draft Guidance as of October 2017. (2017).
    1. European Medicines Agency. Guideline on the investigation of drug interactions CPMP/EWP/560/95/Rev. 1 Corr. 2**, 21 June 2012. (2012).
    1. Ma JD, et al. Evaluation of in vivo P-glycoprotein phenotyping probes: A need for validation. Clin. Pharmacokinet. 2010;49:223–237.
    1. Koup JR, Greenblatt DJ, Jusko WJ, Smith TW, Koch-Weser J. Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses. J. Pharmacokinet. Biopharm. 1975;3:181–192.
    1. Greiner B, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 1999;104:147–153.
    1. Pedersen KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Pedersen KK. The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur. J. Clin. Pharmacol. 1982;22:123–127.
    1. He J, Yu Y, Prasad B, Chen X, Unadkat JD. Mechanism of an unusual, but clinically significant, digoxin–bupropion drug interaction. Biopharm. Drug Dispos. 2014;35:253–263.
    1. Fuhr U, Hsin C, Li X, Jabrane W, Sörgel F. Assessment of pharmacokinetic drug–drug interactions in humans: In vivo probe substrates for drug metabolism and drug transport revisited. Annu. Rev. Pharmacol. Toxicol. 2019;59:507–536.
    1. Scotcher D, Jones CR, Galetin A, Rostami-Hodjegan A. Delineating the role of various factors in renal disposition of digoxin through application of physiologically based kidney model to renal impairment populations. J. Pharmacol. Exp. Ther. 2017;360:484–495.
    1. Sato T, Mishima E, Mano N, Abe T, Yamaguchi H. Potential drug interactions mediated by renal organic anion transporter OATP4C1. J. Pharmacol. Exp. Ther. 2017;362:271–277.
    1. Penzak SR, et al. Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes. Ther. Drug Monit. 2004;26:322–330.
    1. Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of genetic polymorphisms of ABCB1 (MDR1, P-glycoprotein) on drug disposition and potential clinical implications: Update of the literature. Clin. Pharmacokinet. 2015;54:709–735.
    1. Gerloff T, et al. MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br. J. Clin. Pharmacol. 2002;54:610–616.
    1. Johne A, et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin. Pharmacol. Ther. 2002;72:584–594.
    1. Verstuyft C, et al. Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur. J. Clin. Pharmacol. 2003;58:809–812.
    1. Hoffmeyer S, et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. 2000;97:3473–3478.
    1. Xu P, Jiang ZP, Zhang BK, Tu JY, Li HD. Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology. 2008;82:221–227.
    1. Kurzawski M, Bartnicka L, Florczak M, Górnik W, Droździk M. Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients. Pharmacol. Rep. 2007;59:107–111.
    1. Tounsi N, et al. ABCB1 and SLCO1B3 gene polymorphisms and their impact on digoxin pharmacokinetics in atrial fibrillation patients among the Tunisian population. Pharmacology. 2017;99:250–258.
    1. Sakaeda T, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm. Res. 2001;18:1400–1404.
    1. Niemeijer MN, et al. ABCB1 gene variants, digoxin and risk of sudden cardiac death in a general population. Heart. 2015;101:1973–1979.
    1. Verstuyft C, et al. Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition. Clin. Pharmacol. Ther. 2003;73:51–60.
    1. Larsen UL, et al. Human intestinal P-glycoprotein activity estimated by the model substrate digoxin. Scand. J. Clin. Lab. Invest. 2007;67:123–134.
    1. Horinouchi M, et al. Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: Functional relevance to pharmacokinetics of digoxin. Pharm. Res. 2002;19:1581–1585.
    1. Kurata Y, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin. Pharmacol. Ther. 2002;72:209–219.
    1. Wu LX, et al. Combined influence of genetic polymorphism and DNA methylation on ABCB1 expression and function in healthy Chinese males. Eur. J. Drug Metab. Pharmacokinet. 2017;42:627–634.
    1. Morita Y, et al. MDR1 genotype-related duodenal absorption rate of digoxin in healthy Japanese subjects. Pharm. Res. 2003;20:552–556.
    1. Becquemont L, et al. Effect of grapefruit juice on digoxin pharmacokinetics in humans. Clin. Pharmacol. Ther. 2001;70:311–316.
    1. Kim T-E, et al. Effect of green tea catechins on the pharmacokinetics of digoxin in humans. Drug Des. Devel. Ther. 2018;12:2139–2147.
    1. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadée W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet. Genomics. 2005;15:693–704.
    1. Siegsmund M. Association of the P-Glycoprotein transporter MDR1 C3435T polymorphism with the susceptibility to renal epithelial tumors. J. Am. Soc. Nephrol. 2002;13:1847–1854.
    1. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim. Biophys. Acta Proteins Proteomics. 2009;1794:860–871.
    1. Kim R, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 2001;70:189–199.
    1. Morita N, Yasumori T, Nakayama K. Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem. Pharmacol. 2003;65:1843–1852.
    1. Kroetz DL, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003;13:481–494.
    1. Leschziner G, et al. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance. Pharmacogenet. Genomics. 2006;16:439–450.
    1. Dickens D, Owen A, Alfirevic A, Pirmohamed M. ABCB1 single nucleotide polymorphisms (1236C>T, 2677G>T, and 3435C>T) do not affect transport activity of human P-glycoprotein. Pharmacogenet. Genomics. 2013;23:314–323.
    1. Trueck C, et al. A clinical DDI study assessing a novel drug transporter phenotyping cocktail with adefovir, sitagliptin, metformin, pitavastatin and digoxin. Clin. Pharmacol. Ther. 2019 doi: 10.1002/cpt.1564.
    1. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR. ABCB1 genotype and PGP expression, function and therapeutic drug response: A critical review and recommendations for future research. Pharmacogenomics J. 2007;7:154–179.
    1. Marzolini C, Tirona RG, Kim RB. Pharmacogenomics of the OATP and OAT families. Pharmacogenomics. 2004;5:273–282.
    1. Hausner H, et al. Effect of semaglutide on the pharmacokinetics of metformin, warfarin, atorvastatin and digoxin in healthy subjects. Clin. Pharmacokinet. 2017;56:1391–1401.
    1. Kirby BJ, et al. Complex drug interactions of the HIV protease inhibitors 3: Effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab. Dispos. 2012;40:610–616.
    1. Weiss M, Sermsappasuk P, Siegmund W. Modeling the kinetics of digoxin absorption: Enhancement by P-glycoprotein inhibition. J. Clin. Pharmacol. 2012;52:381–387.
    1. Gazzaz M, et al. Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2, and P-glycoprotein activities but somewhat inhibits CYP1A2, CYP2D6, and intestinal CYP3A: So what? Clin. Pharmacol. Ther. 2018;104:1249–1259.
    1. Yin OQP, Tomlinson B, Chow MSS. Effect of multidrug resistance gene-1 (ABCB1) polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men. Clin. Ther. 2009;31:999–1006.
    1. Sai K, et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics. 2003;13:741–757.
    1. Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics. 2003;13:89–95.
    1. Taegtmeyer AB, et al. ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation. Transplantation. 2010;89:75–82.
    1. Wang Y, et al. Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. Eur. J. Clin. Pharmacol. 2009;65:239–247.
    1. Mai I, et al. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J. Clin. Pharmacol. 2003;43:1101–1107.
    1. Bocci G, et al. New insights in the in vitro characterisation and molecular modelling of the P-glycoprotein inhibitory promiscuity. Eur. J. Pharm. Sci. 2018;121:85–94.
    1. Chu X, et al. Clinical probes and endogenous biomarkers as substrates for transporter drug–drug interaction evaluation: Perspectives from the international transporter consortium. Clin. Pharmacol. Ther. 2018;104:836–864.
    1. Barnett S, et al. Gaining mechanistic insight into coproporphyrin I as endogenous biomarker for OATP1B-mediated drug–drug interactions using population pharmacokinetic modeling and simulation. Clin. Pharmacol. Ther. 2018;104:564–574.
    1. Marques P, et al. P-glycoprotein influences urinary excretion of aldosterone in healthy individuals. J. Hypertens. 2019;37:2225–2231.
    1. Bengtsson H, Wirapati P, Speed TP. A single-array preprocessing method for estimating full-resolution raw copy numbers from all affymetrix genotyping arrays including GenomeWideSNP 5 & 6. Bioinformatics. 2009;25:2149–2156.
    1. U.S. Food and Drug Administration. Bioanalytical method validation guidance for industry. (2018).
    1. European Medicines Agency. Guideline on bioanalytical method validation EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**, 21 July 2011. (2011).
    1. Hadley Wickham. tidyverse: Easily Install and Load the ‘Tidyverse’ (2017).
    1. Jonsson EN, Karlsson MO. Xpose—An S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput. Methods Programs Biomed. 1999;58:51–64.

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