Thiazolidinediones toxicity

Haskins, J.R., Rowse, P., Rahbari, R. and de La Iglesia, F.A. (2001) Thiazolidinedione toxicity to isolated hepatocytes revealed by coherent multiprobe fluorescence microscopy and correlated with multiparameter flow cytometry of peripheral leukocytes. Archives of Toxicology, 75, 425-438. 

Two thiazolidinediones are currently available pioglitazone and rosiglitazone (Table 41-8). Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. An earlier compound, troglitazone, was withdrawn from the market because of hepatic toxicity thought to be related to its side chain. 

Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia) Similar to the biguanides (metformin) Headache dizziness fatigue/weakness back pain rare but potentially severe cases of hepatic toxicity... 

Administration of high dose of thiazolidinedione PPARy agonists to animals has reportedly resulted in a number distinct toxic effects, such... 

However the development of inhibitors for PTPs with suitable drug-like features of selectivity, absorption, distribution, metabolism, excretion and toxicity (ADMET) has proven to be challenging in part due to the highly conserved and charged active site [39]. A potent inhibitor of human low molecular weight protein tyrosine phosphatase is a 3-phenoxyphenyl derivative of an 5 -arylidene-2,4-thiazolidinedione [40]. 

The thiazolidinediones (glitazones) act via peroxisome proliferation activating receptors that control insulin-responsive genes. They are less hypoglycemic than the sulfonyiureas, but they still induce j weight gain and edema and have potential liver toxicity. 

Toxicities When these drugs are used alone, hypoglycemia is extremely rare. Thiazolidinediones can cause edema and mild anemia. Pioglitazone and troglitazone appear to induce cytochrome P450 (especially the 3A4 isozyme) and can reduce the serum concentrations of drugs that are metabolized by these enzymes (eg, oral contraceptives, cyclosporine). 

The manufacturers recommend that because bexarotene is related to vitamin A, any vitamin A supplements should be limited to 15 000 units or less daily to avoid potentially additive toxic effects. They also say that although no cases of hypoglycaemia have been seen, because of the known mode of action of bexarotene it should be used with caution if given with insulin or drugs that enhance insulin secretion (e.g. sulfonylure-as) or insulin sensitisers (e.g. thiazolidinediones). For a list of these drugs see Table 13.1 , (p.469). 

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