Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition.
OBJECTIVE
Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates.


METHODS
Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration.


RESULTS
Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration.


CONCLUSIONS
Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.
Siegmund
Werner
W
Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, University of Greifswald, Greifswald, Germany. siegmuw@uni-greifswald.de
Altmannsberger
Stephan
S
Paneitz
Andrea
A
Hecker
Ute
U
Zschiesche
Michael
M
Franke
Gerd
G
Meng
Wieland
W
Warzok
Rolf
R
Schroeder
Eike
E
Sperker
Bernhard
B
Terhaag
Bernd
B
Cascorbi
Ingolf
I
Kroemer
Heyo K
HK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D004386:Duodenum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018709:Statistics, Nonparametric; D013974:Thyroxine / Q000008:administration & dosage*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D004364:Pharmaceutical Preparations; D011412:Propanolamines; D012333:RNA, Messenger; C011550:talinolol; D013974:Thyroxine