Drugs and the Peroxisome Proliferator Activated Receptors
Pp. 149-210 (62)
Kevin Stuart, Andrew Hartland, Mithun Bhartia and Sudarshan Ramachandran
Fibrates and thiazolidinediones, modulators of PPARα and γ nuclear
receptors respectively, are classes of drugs in current use. Their use in clinical medicine
has varied depending on the evidence at the time. There have been agents within each
group that have been withdrawn due to concern of adverse events. In the case of fibrates
there possibly is a current resurgence based on early evidence of microvascular benefit
in patients with T2DM. The use of pioglitazone, the only thiazolidinedione marketed,
appears to be on the wane due to possible associations with cancer having already led to
its withdrawal in certain countries. The dual PPARα/γ agonists are not in current use
with muraglitazar and tessaglitazar withdrawn for differing reasons. Furthermore there
is the possibility of PPARß/δ activators being developed.
It is clear that heterogeneity even within a class of drug exists and this may be
dependent not just on the pharmacokinetics and pharmacodynamics of the drug, but also
the complexity of the PPAR receptor with associated effects. We hope that this brief
chapter, including a description of gene expression, nuclear receptors followed by
details of PPAR and their ligands, will leave the reader with an appreciation of the
complexity that PPAR agonism leads to and the heterogeneity of effects that has added
to some of the confusion existing.
Cholesterol, co-activators, co-repressor, fatty acids, fibrates, gene
expression, glitazars, HDL-C, lipid metabolism, metabolic syndrome, nuclear receptors,
paradoxical HDL-C change, PPARα, PPARβ/δ, PPARγ, randomised controlled
trials/meta-analysis, statins, thiazolidinediones, triglycerides, Type 2 diabetes.
Department of Clinical Biochemistry, Good Hope Hospital, Heart of England NHS Foundation Trust, Rectory Road, Sutton Coldfield, West Midlands, B75 7RR, United Kingdom.