Abstract
Purpose. To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects.
Methods. The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg.
Results. It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C), 52.6 % (60/114) were compound heterozygotes with a mutant T-allele (C3435T) (C/T), and 12.3 % (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC0-4 h values (±SD) were 4.11 ± 0.57, 3.20 ± 0.49, and 3.27± 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T.
Conclusions. The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.
Similar content being viewed by others
REFERENCES
R. L. Juliano and V. Ling. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455:152-162 (1976).
K. Ueda, A. Yoshida, and T. Amachi. Recent progress in P-glycoprotein research. Anti-Cancer Drug Design 14:115-121 (1999).
C. Ramachandran and S. J. Melnick. Multidrug resistance in human tumors—molecular diagnosis and clinical significance. Mol. Diagnosis 4:81-94 (1999).
K. Ueda, D. P. Clark, C. Chen, I. B. Roninson, M. M. Gottesman, and I. Pastan. The human multudrug resistance (mdr1) gene. J. Biol. Chem. 262:505-508 (1987).
K. Ueda, C. Cardarelli, M. M. Gottesman, and I. Pastan. Expression of full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl. Acad. Sci. USA 84:3004-3008 (1987).
F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multdrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735-7738 (1987).
H. Kurihara, H. Suzuki, and Y. Sugiyama. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87:1025-1040 (1998).
Y. Tanigawara. Role of P-glycoprotein in drug disposition. Ther. Drug Monit. 22:137-140 (2000).
P. Borst, A. H. Schinkel, J. J. M. Smit, E. Wagenaar, L. van Deemter, A. J. Smith, E. W. H. M. Eijdems, F. Baas, and G. J. R. Zaman. Classical and novel forms of multidrug resistance and the physiological functions of P-glycoproteins in mammals. Pharmacol. Ther. 60:289-299 (1993).
J. Hunter and B. H. Hirst. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Adv. Drug Deliv. Rev. 25:129-157 (1997).
S. Hoffmeyer, O. Burk, O. von Richter, H. P. Arnold, J. Brockmoller, A. Johne, I. Cascorbi, T. Gerloff, I. Roots, M. Eichelbaum, and U. Brinkmann. 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. USA 97:3473-3478 (2000).
B. Greiner, M. Eichelbaum, P. Fritz, H.-P. Kreichgauer, O. von Richer, J. Zundler, and H. K. Kroemer. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 104:147-153 (1999).
A. Johne, J. Brockmoller, S. Bauer, A. Maurer, M. Langheinrich, and I. Roots. Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin. Pharmacol. Ther. 66:338-345 (1999).
L. Wang, K. Hirayasu, M. Ishizawa, and Y. Kobayashi. Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated NaI and SDS. Nucleic Acids Res. 22:1774-1775 (1994).
G. J. Buffone and G. J. Darlington. Isolation of DNA from biological specimens without extraction with phenol. Clin. Chem. 31:164-165 (1985).
G. Koren. Clinical pharmacokinetic significance of the renal tubular secretion of digoxin. Clin. Pharmacokinet. 13:334-343 (1987).
Y. Tanigawara, N. Okamura, M. Hirai, M. Yasuhara, K. Ueda, N. Kioka, T. Komano, and R. Hori. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J. Pharmacol. Exp. Ther. 263:840-845 (1992).
K. Ueda, N. Okamura, M. Hirai, Y. Tanigawara, T. Saeki, N. Kioka, T. Komano, and R. Hori. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J. Biol. Chem. 267:24248-24252 (1992).
A. H. Schinkel, J. J. M. Smit, O. van Tellingen, J. H. Beijnen, E. Wagenaar, L. van Deemter, C. A. A. M. Mol, M. A. van der Valk, E. C. Robanus-Maandag, H. P. J. te Riele, A. J. M. Berns, and P. Borst. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increases sensitivity to drugs. Cell 77:491-502 (1994).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sakaeda, T., Nakamura, T., Horinouchi, M. et al. MDR1 Genotype-Related Pharmacokinetics of Digoxin After Single Oral Administration in Healthy Japanese Subjects. Pharm Res 18, 1400–1404 (2001). https://doi.org/10.1023/A:1012244520615
Issue Date:
DOI: https://doi.org/10.1023/A:1012244520615