Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone.
The main metabolites observed in humans are also observed in rats; however, the clearance in rats was almost ten times higher than in humans, probably due to the higher levels of CYP2C in rat microsomes.
In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.
Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.
IDENTIFICATION AND USE: Rosiglitazone is a solid. It is used as an antidiabetic agent as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. HUMAN STUDIES: Thiazolidinediones, including rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and may lead to or exacerbate congestive heart failure (CHF). Use of thiazolidinediones is associated with an approximately twofold increased risk of CHF. No evidence of hepatotoxicity has been noted with rosiglitazone in clinical studies to date, including a long-term (4-6 years) study in patients with recently diagnosed type 2 diabetes mellitus. However, hepatitis, elevations in hepatic enzymes to at least 3 times the upper limit of normal, and liver failure with or without fatalities have been reported during postmarketing experience with rosiglitazone. Rosiglitazone was not mutagenic or clastogenic in the in vitro chromosome aberration test in human lymphocytes. ANIMAL STUDIES: Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses >/= 1.5 mg/kg/day. Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments. Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion. Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day. In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance, or pregnancy incidence in females. Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
In contrast to troglitazone, rosiglitazone is not associated with an increased frequency of aminotransferase elevations during therapy. In clinical trials, ALT elevations above 3 times the ULN occurred in only 0.25% of patients on rosiglitazone, compared to 0.25% of placebo recipients (and 1.9% of troglitazone recipients in similar studies). In addition, clinically apparent liver injury attributed to rosiglitazone is very rare, fewer than a dozen cases having been described in the literature despite extensive use of this agent. The liver injury usually arises between 1 and 12 weeks after starting therapy (thus, a shorter latency than typically occurs with troglitazone) and all patterns of serum enzyme elevations have been described including hepatocellular, cholestatic and mixed. Allergic phenomena are rare and autoantibodies have not been typically present. Fatal instances have been reported usually in cases with a hepatocellular pattern of injury. In most instances, recovery is complete within 1 to 2 months.
The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.
Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.
