601 (324)

Absorption: Troglitazone is absorbed rapidly following oral administration; the time for maximum plasma concentration (t_max) occurs within 2 to 3 hours. Food increases the extent of absorption by 30% to 85%, thus Rezulin should be taken with a meal to enhance systemic drug availability.

Distribution: Mean apparent volume of distribution (V/F) of troglitazone following multiple-dose administration ranges from 10.5 to 26.5 Ukg of body weight. Troglitazone is extensively bound ( > 99%) to serum albumin. [¹⁴C] troglitazone partitions into red blood cells (- 5% of whole blood radioactivity).

Metabolism: In 6 healthy male volunteers given a single 400 mg dose of [¹⁴C] troglitazone after 14 days of treatment with 400 mg troglitazone tablets, the major metabolites found in the plasma were the sulfate conjugate (Metabolite 1) followed by the quinone metabolite (Metabolite 3). Only 3.1% of the dose was detected in the urine; this was primarily in the form of the glucuronide conjugate (Metabolite 2), which is present in negligible amounts in the plasma. In both normal volunteers and patients with type II diabetes, steady-state levels of Metabolite 1 are 6 to 7 times that of troglitazone and Metabolite 3.

Troglitazone incubated with expressed human P450 1A1, 1 A2. 2A6. 2B6, 2D6, 2E1, and 3A4 in the presence and absence of known inhibitors of these enzymes showed no Metabolite 3 formation above levels in control samples. Studies in human microsomes suggest that Metabolite 3 is not subject to further metabolism by the major P450 isozymes. Troglitazone did not inhibit any of the major P450 enzymes at clinically relevant concentrations. The inhibitory characteristics of Metabolite 3 have not been investigated directly.

The results of human in vivo drug interaction trials suggest that troglitazone induces cytochrome P450 3A4 at clinically relevant doses (see DRUG INTERACTIONS).

Excretion: Following oral administration of [14 C] troglitazone, approximately 88% of the radioactivity is recovered in feces (85%) and urine (3%). Unchanged troglitazone is not recovered in urine following oral administration. Mean plasma elimination half-life of troglitazone ranges from 16 to 34 hours.

Special Populations

Renal Insufficiency: In patients with various degrees of renal function, the apparent clearance of total and unbound troglitazone and the plasma elimination half-life of troglitazone, Metabolite 1, and Metabolite 3 do not correlate with creatinine clearance. Thus, dose adjustment in patients with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Troglitazone, Metabolite 1, and Metabolite 3 plasma concentrations in patients with chronic liver disease (Childs-Pugh Grade B or C) were increased by approximately 30%, 40 % and 100% respectively, compared to those in healthy subjects without hepatic dysfunction. There was no change in plasma protein binding. No adverse events were noted in any group that were attributed to drug. However, Rezulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT> 3 times the upper limit of normal); see WARNINGS.

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