The effect of ranitidine on the pharmacokinetics of rosiglitazone in healthy adult male volunteers.
BACKGROUND
Rosiglitazone is an insulin-sensitizing oral agent in the thiazolidinedione class used to treat patients with type 2 diabetes mellitus. It binds to peroxisome proliferator-activated receptor gamma in liver, muscle, and adipose tissue. Ranitidine, a histamine2-receptor antagonist, may be prescribed for patients with type 2 diabetes and esophageal symptoms such as heartburn. By raising gastrointestinal pH levels, ranitidine may affect the bioavailability of coadministered drugs.


OBJECTIVE
This article presents the absolute bioavailability of rosiglitazone, as well as the effects of ranitidine on the pharmacokinetics of rosiglitazone.


METHODS
Healthy men were enrolled in a randomized, open-label, 4-period, period-balanced crossover study of rosiglitazone and ranitidine. All individuals received each of 4 regimens successively, separated by a 4-day washout period: a single IV dose of rosiglitazone 2 mg administered alone over 1 hour; a single IV dose of rosiglitazone 2 mg administered over 1 hour on the fourth day of treatment with oral ranitidine 150 mg given every 12 hours; a single oral dose of rosiglitazone 4 mg alone; and a single oral dose of rosiglitazone 4 mg on the fourth day of treatment with oral ranitidine 150 mg given every 12 hours. The primary end point was dose-normalized area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). Maximum observed plasma concentration (Cmax), the time at which Cmax occurred (Tmax), plasma clearance (CL), steady-state volume of distribution (Vss), and terminal elimination half-life (t 1/2) were also assessed.


RESULTS
Twelve individuals were enrolled. The absolute bioavailability of rosiglitazone was 99%. For AUC(0-infinity), the point estimate and the associated 95% CI for the ratio of ranitidine + IV rosiglitazone to IV rosiglitazone alone was 1.02 (range, 0.88-1.20). With oral rosiglitazone, the AUC(0-infinity) point estimate (95% CI) for the ratio of ranitidine + rosiglitazone to rosiglitazone alone was 0.99 (range, 0.85-1.16). Cmax, Tmax, t 1/2, Vss and CL of rosiglitazone, whether administered orally or intravenously, were unaffected by ranitidine. Oral and IV rosiglitazone were associated with a favorable safety profile and were well tolerated with or without concurrent ranitidine treatment.


CONCLUSIONS
In this study of 12 healthy adult male volunteers, the absolute bioavailability of rosiglitazone was 99%, and the oral and IV single-dose pharmacokinetics of rosiglitazone were unaltered by concurrent treatment with ranitidine.
Miller
Ann K
AK
GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. ann.k.miller@gsk.com
DiCicco
Robert A
RA
Freed
Martin I
MI
D000284:Administration, Oral; D000328:Adult; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D011899:Ranitidine / Q000494:pharmacology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045162:Thiazolidinediones
D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011899:Ranitidine