indication

Treatment of Type II diabetes mellitus

pharmacology

Pioglitazone, a member of the drug group known as the thiazolidinediones or "insulin sensitizers", is not chemically or functionally related to the alpha-glucosidase inhibitors, the biguanides, or the sulfonylureas. Pioglitazone targets insulin resistance and, hence, is used alone or in combination with insulin, metformin, or asulfonylurea as an antidiabetic agent.

mechanism of action

Pioglitazone acts as an agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors increases the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, pioglitazone both enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis. Thus, insulin resistance associated with type 2 diabetes mellitus is improved without an increase in insulin secretion by pancreatic β cells.

toxicity

Hypogycemia; LD₅₀=mg/kg (orally in rat)

biotransformation

Hepatic

absorption

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

half life

3-7 hours

route of elimination

Following oral administration, 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 eliminated in the feces.

drug interactions

Colesevelam: Bile Acid Sequestrants may decrease the absorption of Antidiabetic Agents (Thiazolidinedione). Separate the dosing of bile acid sequestrants and thiazolidinediones by at least 2 hours. Monitor for reduced effects of the antidiabetic agents.

Gemfibrozil: Gemfibrozil may increase the effect and toxicity of pioglitazone.

Glucosamine: Possibly hyperglycemia

Ketoconazole: Ketoconazole increases the effect of pioglitazone

Mestranol: Possible loss of contraceptive effect

Norethindrone: Possible loss of contraceptive effect

Somatropin recombinant: Somatropin may antagonize the hypoglycemic effect of pioglitazone. Monitor for changes in fasting and postprandial blood sugars.

Tamoxifen: Pioglitazone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Pioglitazone, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Pioglitazone is initiated, discontinued, or dose changed.

Tramadol: Pioglitazone may decrease the effect of Tramadol by decreasing active metabolite production.

Tretinoin: The moderate CYP2C8 inhibitor, Pioglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Pioglitazone is initiated, discontinued to dose changed.