Gemfibrozil considerably increases the plasma concentrations of rosiglitazone.
OBJECTIVE
Our aim was to investigate possible interaction between gemfibrozil and rosiglitazone, a thiazolidinedione antidiabetic drug.


METHODS
In a randomised crossover study with two phases, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 4 days. On day 3, they ingested a single 4 mg dose of rosiglitazone. Plasma rosiglitazone and its N-desmethyl metabolite concentrations were measured for up to 48 h.


RESULTS
Gemfibrozil raised the mean area under the plasma rosiglitazone concentration-time curve (AUC) 2.3-fold (range 1.5- to 2.8-fold; p=0.00002) and prolonged the elimination half-life (t(1/2)) of rosiglitazone from 3.6 to 7.6 h ( p=0.000002). The peak plasma rosiglitazone concentration (C(max)) was increased only 1.2-fold (range 0.9- to 1.6-fold; p=0.01) by gemfibrozil, but gemfibrozil raised the plasma rosiglitazone concentration measured 24 h after dosing (C(24)) 9.8-fold (range, 4.5- to 33.6-fold; p=0.00008). In addition, gemfibrozil prolonged the t(max) of N-desmethylrosiglitazone from 7 to 12 h and reduced the N-desmethylrosiglitazone/rosiglitazone AUC(0-48) ratio by 38% ( p<0.01).


CONCLUSIONS
Gemfibrozil raises the plasma concentrations of rosiglitazone probably by inhibiting the CYP2C8-mediated biotransformation of rosiglitazone. Co-administration of gemfibrozil, or another potent inhibitor of CYP2C8, and rosiglitazone could increase the efficacy but also the risk of concentration-dependent adverse effects of rosiglitazone.
Niemi
M
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Backman
J T
JT
Granfors
M
M
Laitila
J
J
Neuvonen
M
M
Neuvonen
P J
PJ
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D015248:Gemfibrozil / Q000097:blood / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood*; D000960:Hypolipidemic Agents / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009994:Osmolar Concentration; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000097:blood*; D013997:Time Factors
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; C480687:N-desmethylrosiglitazone; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015248:Gemfibrozil