Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

被引:41
作者
Yokogawa, K [1 ]
Shimada, T [1 ]
Higashi, Y [1 ]
Itoh, Y [1 ]
Masue, T [1 ]
Ishizaki, J [1 ]
Asahi, M [1 ]
Miyamoto, K [1 ]
机构
[1] Kanazawa Univ, Sch Med, Dept Hosp Pharm, Kanazawa, Ishikawa, Japan
关键词
dexamethasone; cyclosporin A; P-glycoprotein; mdr1a; CYP3A2; expression; pharmacokinetics;
D O I
10.1016/S0006-2952(01)00911-X
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We investigated the effect of dexamethasone (DEX) on the disposition kinetics of cyclosporin A (CyA) and the mechanism of this drug interaction. Rats were treated with DEX (I or 75 mg/kg per day, i.p.) once a day for 1-7 days, and the blood concentration of CyA was measured after an i.v. or p.o. dose of CyA (10 mg/kg) at 1.5 hr after the last DEX treatment. In rats treated with a low dose of DEX (1 mg/kg), the blood concentration of CyA after i.v. administration was unchanged compared with that of untreated rats, whereas the blood concentration after oral administration was significantly decreased, and this decrease was dependent on the duration of DEX administration. The total clearance (CLtot) of CyA was unchanged, but the bioavailability was significantly decreased to about one-third of that in DEX-untreated rats after 7 days of DEX treatment. At this time, the expression of mdr1a mRNA and P-gp in the liver and intestine was increased, whereas CYP3A2 was unaffected at both the mRNA and protein levels, In rats treated with a high dose of DEX (75 mg/kg), the blood concentration of CyA was significantly decreased after both i.v. and p.o. administrations compared with those of untreated rats. The bioavailability of CyA was decreased, and the CLtot was significantly increased. The P-gp and CYP3A2 in the liver and intestine were increased at both the mRNA and protein levels. Our results indicate that the drug interaction between CyA and DEX is a consequence of modulation of P-gp and CYP3A2 gene expression by DEX, with differential dose-dependence. (C) 2002 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:777 / 783
页数:7
相关论文
共 33 条
  • [1] STRUCTURE AND EXPRESSION OF THE HUMAN MDR (P-GLYCOPROTEIN) GENE FAMILY
    CHIN, JE
    SOFFIR, R
    NOONAN, KE
    CHOI, K
    RONINSON, IB
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (09) : 3808 - 3820
  • [2] David-Neto E, 2000, Rev Hosp Clin Fac Med Sao Paulo, V55, P207
  • [3] Dexamethasone modulation of multidrug transporters in normal tissues
    Demeule, M
    Jodoin, J
    Beaulieu, E
    Brossard, M
    Béliveau, R
    [J]. FEBS LETTERS, 1999, 442 (2-3) : 208 - 214
  • [4] 2 MEMBERS OF THE MOUSE MDR GENE FAMILY CONFER MULTIDRUG RESISTANCE WITH OVERLAPPING BUT DISTINCT DRUG SPECIFICITIES
    DEVAULT, A
    GROS, P
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (04) : 1652 - 1663
  • [5] DEWAZIERS I, 1990, J PHARMACOL EXP THER, V253, P387
  • [6] PHARMACOKINETIC DETERMINANTS OF CYCLOSPORINE AND PREDNISONE IN RENAL-TRANSPLANT PATIENTS
    FREY, FJ
    HARRINGTON, JT
    COGAN, M
    VINCENTI, F
    BENET, LZ
    AMEND, WJC
    GAMBERTOGLIO, J
    STEMPEL, C
    HALE, V
    HULTER, H
    HUMPHREYS, M
    HOLFORD, NV
    [J]. KIDNEY INTERNATIONAL, 1991, 39 (05) : 1034 - 1050
  • [7] DETECTION OF P-GLYCOPROTEIN ISOFORMS BY GENE-SPECIFIC MONOCLONAL-ANTIBODIES
    GEORGES, E
    BRADLEY, G
    GARIEPY, J
    LING, V
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (01) : 152 - 156
  • [8] The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin
    Greiner, B
    Eichelbaum, M
    Fritz, P
    Kreichgauer, HP
    Von Richter, O
    Zundler, J
    Kroemer, HK
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1999, 104 (02) : 147 - 153
  • [9] ISOLATION AND EXPRESSION OF A COMPLEMENTARY-DNA THAT CONFERS MULTIDRUG RESISTANCE
    GROS, P
    BEN-NERIAH, Y
    CROOP, JM
    HOUSMAN, DE
    [J]. NATURE, 1986, 323 (6090) : 728 - 731
  • [10] ESTIMATION OF ISOZYMES OF MICROSOMAL CYTOCHROME-P-450 IN RATS, RABBITS, AND HUMANS USING IMMUNOCHEMICAL STAINING COUPLED WITH SODIUM DODECYL-SULFATE POLYACRYLAMIDE-GEL ELECTROPHORESIS
    GUENGERICH, FP
    WANG, P
    DAVIDSON, NK
    [J]. BIOCHEMISTRY, 1982, 21 (07) : 1698 - 1706