Predictive power of an in vitro system to assess drug interactions of an antimuscarinic medication: a comparison of in vitro and in vivo drug-drug interaction studies of trospium chloride with digoxin.
The authors studied a potential drug-drug interaction via findings from in vitro and in vivo studies, to assess whether the in vitro system was predictive of in vivo clinical pharmacokinetic outcomes. An in vitro experiment and a clinical study were performed to assess the potential for interaction. The effect of trospium chloride on human P-glycoprotein-mediated transport of [3H]-digoxin was determined in vitro. A randomized, crossover clinical trial in 40 subjects was performed to evaluate the effect of trospium on the pharmacokinetics of digoxin in vivo. The findings from the studies were then compared. The in vitro findings in this study were corroborated by the clinical study via assessment of inhibition and impact on pharmacokinetic parameters. The in vitro system for assessment of a potential interaction of 2 drugs excreted primarily through the kidney was predictive of the pharmacokinetic outcomes obtained from a clinical setting.
Sandage
B
B
Indevus Pharmaceuticals Inc, 33 Hayden Avenue, Lexington, MA 02421, USA. bsandage@indevus.com
Sabounjian
L
L
Shipley
J
J
Profy
A
A
Lasseter
K
K
Fox
L
L
Harnett
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D001561:Benzilates; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004077:Digoxin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009662:Nortropanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011237:Predictive Value of Tests; D012016:Reference Values; D013552:Swine; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001561:Benzilates; D002316:Cardiotonic Agents; D018727:Muscarinic Antagonists; D009662:Nortropanes; C003330:trospium chloride; D004077:Digoxin; D007654:Ketoconazole