Management of Diabetes: PHARMACOKINETICS


Both rosiglitazone and generic pioglitazone are well absorbed with excellent bioavailability. The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations of rosiglitazone are observed about one hour after dosing, whereas pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within two hours. Administration of both agents with food results in no clinically significant pharmaco-kinetic alterations.

The maximum plasma concentration (Cmax) and the area-under-the-curve (AUC) concentration of generic rosiglitazone and pio-glitazone increase in a dose-proportional manner over the therapeutic dose range. Both drugs achieve a similar Cmax and show a linear increase in plasma drug concentration with elevated doses.

The time to peak concentration (Tmax) is another important parameter to consider. The more rapidly an orally administered agent can reach Cmax, the more closely its concentration curve will follow that of intravenous (IV) dosing. The absorption characteristics of these two agents appear to be similar.


Protein-binding affinity is thought to be significant in establishing a drug’s volume of distribution (Vd). The Vd estimates the theoretical body space available for the distribution of a drug. A Vd greater than 1 liter/kg indicates penetration beyond the vasculature. Rosiglitazone, and its active metabolites are extensively protein-bound (by more than 98%). The mean apparent volume of distribution (Vd/F) of pioglitazone following a single-dose administration is 0.63 ± 0.41 (mean ± SD) liters/kg of body weight.

The mean oral steady-state volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. These differences may not translate into the clinical effectiveness of the agents.


Following oral administration, rosiglitazone and pioglitazone are eliminated by both renal and nonrenal routes. Approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile, either unchanged or as metabolites, and is eliminated in the feces.

After oral or intravenous administration of carbon 14 (C)-rosiglitazone maleate, approximately 64% of the dose is eliminated in the urine and 23% is eliminated in the feces. The elimination half-life of is three to four hours and is independent of the dose. The plasma half-life of C-rosi-glitazone material ranges from 103 to 158 hours. The mean serum half-life of pioglitazone ranges from 3 to 7 hours; for total pioglitazone, the range is 16 to 24 hours.

Pioglitazone has an apparent clearance (CL/F) that has been calculated to be 5 to 7 liters/hour. The mean Cmax and AUC values are increased by 20% to 60% in female patients. Because therapy should be tailored for each patient to achieve glycemic control, no dose adjustment is recommended based on sex alone.

Pioglitazone therapy should not be initiated if there is clinical evidence of active liver disease or if serum alanine transaminase (ALT) levels exceed 2.5 times the upper limit of normal.

Drug-Drug Interactions

Interactions with some drugs can reduce the agent’s intestinal absorption, thereby affecting efficacy. In vivo drug-drug interaction studies have suggested that pio-glitazone may be a weak inducer of the cytochrome P450 (CYP450) isoform 3A4 enzyme. CYP3A4 is common to the metabolism of many drugs, including some immunosuppressive agents. Consequently, there might be some potential interaction between pioglitazone and post-transplantation immunosuppressive drugs. canadian pharmacy viagra

In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major cytochrome P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8 and, to a lesser extent, CYP2C9. Coadministration of pioglitazone 45 mg once daily for 15 days, followed by a single 7.5-mg dose of midazolam syrup, resulted in a 26% reduction in the midazolam Cmax and AUC concentration. Administration of another TZD with an oral contraceptive containing ethinyl estradiol and norethindrone reduces the plasma concentrations of both hormones by approximately 30%, which can result in loss of contraception.

Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive. However, rosiglitazone 4 mg twice daily had no clinically relevant effect on the pharmacokinetics of ethinyl estradiol and norethindrone.

Drug-Food Interactions

The TZDs are not affected significantly by coadministration of food. Taking both agents with food results in no clinically significant pharmacokinetic alterations.

Category: Diabetes

Tags: Diabetes, diabetes mellitus

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