DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1260 and their specific role in therapeutics. Table 43–8 compares
metformin and thiazolidinediones.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
PPARγ is expressed primarily in adipose tissue with lesser
expression in cardiac, skeletal, and smooth muscle cells, islet β cells,
macrophages, and vascular endothelial cells. The endogenous ligands
for PPARγ include small lipophilic molecules such as oxidized
linoleic acid, arachidonic acid and the prostaglandin metabolite 15d-
PGJ2; rosiglitazone and pioglitazone are synthetic ligands for
PPARγ. Ligand binding to PPARγ causes heterodimer formation
with the retinoid X receptor and interaction with PPAR response elements
on specific genes, an interaction that is modulated by complex
interactions with co-repressors and co-activators. The principal
response to PPARγ activation is adipocyte differentiation. Preclinical
gain-of-function models show increased numbers of adipocytes and
expansion of fat mass; loss-of-function models demonstrate lipodystrophy.
Along with adipocyte differentiation, PPARγ activity promotes
uptake of circulating fatty acids into fat cells and shifts of lipid
stores from extra-adipose to adipose tissue. One consequence of the
concerted cellular responses to PPARγ activation is increased tissue
sensitivity to insulin, and this is the basis for the pharmacological
application of thiazolidinediones to clinical medicine.
Pioglitazone and rosiglitazone are insulin sensitizers and
increase insulin-mediated glucose uptake by 30-50% in patients with
type 2 diabetes. Although adipose tissue seems to be the primary target
for PPARγ agonists, both clinical and preclinical models support
a role for skeletal muscle, the major site for insulin-mediated glucose
disposal, in the response to thiazolidinediones. It is still not clear
whether thiazolidinedione-induced improvement of insulin resistance
is due to direct effects on key target tissues (skeletal muscle
and liver), indirect effects mediated by secreted products of
adipocytes (e.g., adiponectin), or some combination of these. In addition
to promoting glucose uptake into muscle and adipose tissue, the
thiazolidinediones reduce hepatic glucose production and increase
hepatic glucose uptake.
Beyond effects on insulin sensitivity and blood glucose, thiazolidinediones
also affect lipid metabolism. Treatment with rosiglitazone
or pioglitazone reduces plasma levels of fatty acids by
increasing clearance and reducing lipolysis. These drugs also cause
a shift of triglyceride stores from nonadipose to adipose tissues, and
from visceral to subcutaneous fat depots. In clinical trials, pioglitazone
reduces plasma triglycerides by 10-15%, and raises HDLcholesterol
levels. This has been attributed to a dual effect on PPARα
as well as PPARγ; rosiglitazone does not interact with PPARα and
has minimal effects on plasma triglycerides and cholesterol. Because
of these actions on plasma lipids, and beneficial effects on inflammatory
markers, coagulation, and endothelial function, thiazolidinediones
were predicted to reduce macrovascular complications of
diabetes and insulin resistance. However, recently completed randomized
clinical trials demonstrated a questionable benefit of pioglitazone
(Dormandy et al., 2005), and no effect of rosiglitazone on
major events related to atherosclerosis (Home et al., 2009). Because
thiazolidinediones reduce hepatic triglyceride, they have been
applied to the treatment of nonalcoholic fatty liver disease. Although
results of these studies have been encouraging (Kashi et al., 2008),
the thiazolidinediones are not yet approved for this use.
Absorption, Distribution, and Elimination. Both agents are
absorbed within 2-3 hours, and bioavailability does not seem to be
affected by food. The thiazolidinediones are metabolized by the liver
and may be administered to patients with renal insufficiency, but
should not be used if there is active hepatic disease or significant
elevations of serum liver transaminases. The thiazolidinediones are
metabolized by hepatic CYPs. CYPs 2C8 and 3A4 metabolize
pioglitazone; rosiglitazone is metabolized by CYPs 2C9 and 2C8.
Rifampin induces these enzymes and causes a significant decrease in
plasma concentrations of rosiglitazone and pioglitazone; gemfibrozil
impedes metabolism of the thiazolidinediones and can increase
plasma levels by ~2-fold. It may be prudent to reduce the doses of
the thiazolidinediones when they are used in conjunction with gemfibrozil.
Rosiglitazone and pioglitazone do not seem to significantly
affect the pharmacokinetics of other drugs.
Therapeutic Uses and Dosage. Rosiglitazone and pioglitazone
are dosed once daily. The starting dose of rosiglitazone
is 4 mg and should not exceed 8 mg daily. The
starting dose of pioglitazone is 15-30 mg, up to a maximum
of 45 mg daily. Thiazolidinediones have proven
effects to enhance insulin action on liver, adipose tissue,
and skeletal muscle. These composite effects on glucose
metabolism confer improvements in glycemic control in
persons with type 2 diabetes and cause average reductions
in A1C of 0.5-1.4%. Thiazolidinediones require the presence
of insulin for pharmacological activity and are not
indicated to treat type 1 diabetes. Both pioglitazone and
rosiglitazone are effective as monotherapy and as additive
therapy to metformin, sulfonylureas, or insulin. The
onset of action of thiazolidinediones is relatively slow;
maximal effects on glucose homeostasis develop gradually
over the course of 1-3 months.
There is evidence in drug-naive diabetic subjects that the glucose-lowering
effect of primary treatment with rosiglitazone is more
durable than that of metformin or glyburide (Kahn et al., 2006).
Treatment with rosiglitazone also reduced progression from prediabetes
to type 2 diabetes (Gerstein et al., 2006).
Adverse Effects and Drug Interactions. The most common adverse
effects of the thiazolidinediones are weight gain and edema. Edema
attributable to thiazolidinedione treatment occurs in up to 10% of