title: The impact of thyroid disease on the regulation, expression, and function of ABCB1 (MDR1/P glycoprotein) and consequences for the disposition of digoxin.
abstract: The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56(+) cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Burk
authors.forename: S S
authors.initials: SS
authors.lastname: Brenner
authors.forename: U
authors.initials: U
authors.lastname: Hofmann
authors.forename: H
authors.initials: H
authors.lastname: Tegude
authors.forename: S
authors.initials: S
authors.lastname: Igel
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: M D
authors.initials: MD
authors.lastname: Alscher
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018938:Caco-2 Cells; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006980:Hyperthyroidism / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007037:Hypothyroidism / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D012235:Rhodamines; D013963:Thyroid Hormones; D004077:Digoxin