Chemical formula: C₁₈H₁₉N₃O₃S Molecular mass: 357.427 g/mol PubChem compound: 77999
Rosiglitazone is a selective agonist at the PPARγ (peroxisomal proliferator activated receptor gamma) nuclear receptor and is a member of the thiazolidinedione class of anti-diabetic agents. It reduces glycaemia by reducing insulin resistance at adipose tissue, skeletal muscle and liver.
The antihyperglycaemic activity of rosiglitazone has been demonstrated in a number of animal models of type 2 diabetes. In addition, rosiglitazone preserved ß-cell function as shown by increased pancreatic islet mass and insulin content and prevented the development of overt hyperglycaemia in animal models of type 2 diabetes. Rosiglitazone did not stimulate pancreatic insulin secretion or induce hypoglycaemia in rats and mice. The major metabolite (para-hydroxy-sulphate) with high affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in obese mouse. The clinical relevance of this observation has not been fully elucidated.
Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 99%. Rosiglitazone plasma concentrations peak at around 1 hour after dosing. Plasma concentrations are approximately dose proportional over the therapeutic dose range.
Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), although a small decrease in Cmax (approximately 20% to 28%) and a delay in tmax (ca.1.75 h) were observed compared to dosing in the fasting state. These small changes are not clinically significant and, therefore, it is not necessary to administer rosiglitazone at any particular time in relation to meals. The absorption of rosiglitazone is not affected by increases in gastric pH.
The volume of distribution of rosiglitazone is approximately 14 litres in healthy volunteers. Plasma protein binding of rosiglitazone is high (approximately 99.8%) and is not influenced by concentration or age. The protein binding of the major metabolite (para-hydroxy-sulphate) is very high (>99.99%).
Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulphate and glucuronic acid. The contribution of the major metabolite (para-hydroxy-sulphate) to the overall anti-diabetic activity of rosiglitazone has not been fully elucidated in man and it cannot be ruled out that the metabolite may contribute to the activity. However, this raises no safety concern regarding target or special populations as hepatic impairment is contraindicated and the phase III clinical studies included a considerable number of elderly patients and patients with mild to moderate renal impairment.
In vitro studies demonstrate that rosiglitazone is predominantly metabolised by CYP2C8, with a minor contribution by CYP2C9.
Since there is no significant in vitro inhibition of CYP1A2, 2A6, 2C19, 2D6, 2E1, 3A or 4A with rosiglitazone, there is a low probability of significant metabolism-based interactions with substances metabolised by these P450 enzymes. Rosiglitazone showed moderate inhibition of CYP2C8 (IC50 18 µM) and low inhibition of CYP2C9 (IC50 50 µM) in vitro. An in vivo interaction study with warfarin indicated that rosiglitazone does not interact with CYP2C9 substrates in vivo.
Total plasma clearance of rosiglitazone is around 3 l/h and the terminal elimination half-life of rosiglitazone is approximately 3 to 4 hours. There is no evidence for unexpected accumulation of rosiglitazone after once or twice daily dosing. The major route of excretion is the urine with approximately two-thirds of the dose being eliminated by this route, whereas faecal elimination accounts for approximately 25% of dose. No intact drug is excreted in urine or faeces. The terminal half-life for radioactivity was about 130 hours indicating that elimination of metabolites is very slow. Accumulation of the metabolites in plasma is expected upon repeated dosing, especially that of the major metabolite (para-hydroxy-sulphate) for which an 8-fold accumulation is anticipated.
In the pooled population pharmacokinetic analysis, there were no marked differences in the pharmacokinetics of rosiglitazone between males and females.
In the pooled population pharmacokinetic analysis, age was not found to influence the pharmacokinetics of rosiglitazone to any significant extent.
Population pharmacokinetic analysis including 96 paediatric patients aged 10 to 18 years and weighing 35 to 178 kg suggested similar mean CL/F in children and adults. Individual CL/F in the paediatric population was in the same range as individual adult data. CL/F seemed to be independent of age, but increased with weight in the paediatric population.
In cirrhotic patients with moderate (Child-Pugh B) hepatic impairment, unbound Cmax and AUC were 2- and 3-fold higher than in normal subjects. The inter-subject variability was large, with a 7-fold difference in unbound AUC between patients.
There are no clinically significant differences in the pharmacokinetics of rosiglitazone in patients with renal impairment or end stage renal disease on chronic dialysis.
Adverse effects observed in animal studies with possible relevance to clinical use were as follows: An increase in plasma volume accompanied by decrease in red cell parameters and increase in heart weight. Increases in liver weight, plasma ALT (dog only) and fat tissue were also observed. Similar effects have been seen with other thiazolidinediones.
In reproductive toxicity studies, administration of rosiglitazone to rats during mid-late gestation was associated with foetal death and retarded foetal development. In addition, rosiglitazone inhibited ovarian oestradiol and progesterone synthesis and lowered plasma levels of these hormones resulting in effects on oestrus/menstrual cycles and fertility.
In an animal model for familial adenomatous polyposis (FAP), treatment with rosiglitazone at 200 times the pharmacologically active dose increased tumour multiplicity in the colon. The relevance of this finding is unknown. However, rosiglitazone promoted differentiation and reversal of mutagenic changes in human colon cancer cells in vitro. In addition, rosiglitazone was not genotoxic in a battery of in vivo and in vitro genotoxicity studies and there was no evidence of colon tumours in lifetime studies of rosiglitazone in two rodent species.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
