Modulation of P-Glycoprotein Expression in Hyperthyroid Rat Tissues

Abstract

ABSTRACT:P-glycoprotein (Pgp) is expressed in various normal tissues and plays an important role in drug absorption and disposition. In addition, it is supposed that alterations in the expression levels of Pgp are involved in the inter-and intraindividual variability of pharmacokinetics of many drugs. Since pharmacokinetic properties of various drugs are altered in patients with thyroid disorders, we examined the expression of Pgp and mdr1a/1b mRNA in the kidney, liver, jejunum, and ileum from euthyroid and hyperthyroid rats. Western blot analysis revealed that Pgp expression was markedly increased in the kidney and liver of hyperthyroid rats. In contrast, it was slightly increased in the jejunum and ileum. mdr1a/1b mRNA levels were significantly increased in the kidney of hyperthyroid rats. However, they were not increased in the liver as well as in the jejunum and ileum of hyperthyroid rats. Expression levels of bile salt export pump and mdr2 mRNA were also unchanged in hyperthyroid rat liver. Taken together, these findings suggest that thyroid hormone induces Pgp expression in a tissue-selective manner, and that the modulation of mdr1a/1b mRNA expression in the hyperthyroid state varies among tissues.P-glycoprotein (Pgp) is expressed in various tissues such as brain, liver, kidney, and intestine (Cordon-Cardo et al., 1990;Brady et al., 2002) and plays an important role in defining the pharmacokinetics of many drugs. Pgp functions as a drug efflux pump and exports hydrophobic, bulky drugs such as anticancer agents, cardiac glycosides, ␤-blockers, calcium channel blockers, and immunosuppressants. Since Pgp has a broad substrate recognition, the concomitant administration of drugs often causes drug interactions by inhibiting Pgpmediated transport (Yu, 1999). For example, inhibition of digoxin transport in cultured epithelial cell lines expressing Pgp by various drugs such as quinidine (Tanigawara et al., 1992;Fromm et al., 1999), verapamil (Tanigawara et al., 1992, and cyclosporin A (Okamura et al., 1993) has been reported. We have also demonstrated that the renal clearance of digoxin was decreased in patients receiving a concomitant administration of clarithromycin and, accordingly, the plasma concentration of digoxin was increased (Wakasugi et al., 1998). The mechanism of this interaction was explained by the inhibition of Pgp-mediated tubular secretion of digoxin. On the other hand, recent studies have demonstrated that changes in the expression levels of Pgp affect the pharmacokinetic properties of Pgp substrates. Greiner et al. (1999) reported that rifampin administration induced Pgp expression in the small intestine and reduced the plasma concentration of orally administered digoxin, suggesting that alterations in the expression levels of Pgp are closely involved in the inter-and intraindividual variability of pharmacokinetics of Pgp substrates.Thyroid hormone is secreted from the thyroid gland to maintain normal growth and development, normal body temperature, and normal energy levels. Most of its effect...

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