Rimonabant [,/V-piperino-5-(4-chloro-phenyl)-1-1(2,4-dichlorophenyl)-4-meth-ylpyrazole-3-carvoxamide] is a CB1 antagonist. At low concentrations, it may also act as an inverse agonist.8 At very high concentrations, canadian rimonabant also behaves as a CB2 receptor antagonist, blocks calcium and potassium channels, and may directly affect cellular gap junctions.
Cannabinoid receptors are members of the G-protein coupled receptor (GPCR) superfamily of cell-surface heptahelical receptors. There are currently two types of cannabinoid receptors: CB1 and CB2. CB1 receptors are among the most abundant GPCRs in the brain.
The cannabinoid CB1 receptors are members of the Gi/Go-linked GPCR family. Therefore, activation of these receptors by anandamide (an endogenous cannabinoid agonist) results in a suppression of neuronal excitability and in a release of neurotransmitters. This effect appears to be accomplished through the following mechanisms: inhibition of adenylyl cyclase, inhibition of voltage-sensitive calcium channels, activation of inwardly rectifying potassium channels, and activation of MAP kinase.
Because of the strong presynaptic localization of the CB1 receptors and their inhibition of the calcium channels and adenylyl cyclase, it is thought that the primary function of these receptors is to inhibit neurotransmitter release, specifically gamma-aminobutyric acid (GABA) or glutamate. In a process called retrograde signaling, endocannabinoids are thought to regulate the release of GABA and glutamate. It is theorized that the endocannabinoid system may be over-active in some individuals with obesity, thus contributing to the accumulation of weight and also encouraging nicotine discrimination (preferring it to other com-pounds).
Stimulation of the CB1 receptors is thought to affect central and peripheral action on lipid and glucose metabolism in adipose tissue. Rimonabant helps to regulate food intake, modulates the intake of highly palatable sweet or fatty foods, affects energy balance, and influences nicotine dependence.
Little pharmacokinetic information on rimonabant has been published. Only one poster from a meeting in 2006 described the drug’s pharmacokinetic properties. It is reported that dose proportionality does not appear to deviate with this agent when it is given in doses up to 20 mg/day. After that point, there is a less than dose-proportional increase in exposure.
The bioavailability of generic rimonabant is unknown. The time to maximum concentration (Tmax) is approximately two hours, and the peak concentration (Cmax) is 196 ± 28.1 ng/ml. The volume of distribution (Vd) is larger and the time to steady state is longer in obese individuals (25 days) than in non-obese individuals (13 days). The Cmax and the area-under-the-curve (AUC) concentration are increased when the drug is taken with a high-fat meal. The plasma protein binding of rimona-bant in vitro is high, at more than 99%.
Rimonabant is metabolized by the cytochrome (CYP) 3A enzyme and amidohydrolase pathways in vitro. Administration of canadian ketoconazole (Nizoral Gel, Janssen) with rimonabant resulted in an increase in the AUC by 104% (40%- 197%).
When combined with CYP 3A4 inhibitors, plasma levels of the drug would be expected to increase; therefore, caution with the use of known CYP 3A4 inhibitors is warranted. Although CYP 3A4 inducers have not been investigated, it is anticipated that they would reduce the drug’s plasma levels and, possibly, its efficacy. Rimonabant does not induce or inhibit common CYP enzymes or P-glycoprotein in vitro. 19 It is a mild inhibitor of CYP 2C8. Metabolites of rimona-bant do not contribute to the medication’s effects. Most of the drug (about 86%) is eliminated in the feces unchanged and as metabolites.
The drug’s half-life is longer in obese patients (approximately 16 days) than in non-obese patients (nine days); this difference is believed to result from the larger Vd of obese people. A patient’s sex has no effect on rimonabant’s pharmaco-kinetics.
Table 1 summarizes the pharmaco-kinetic parameters of rimonabant.
Table 1 Pharmacokinetic Profile of Rimonabant
|• Oral bioavailability||Unknown|
|• Tmax||Approximately two (2) hours|
|• Pathway of metabolism||CYP 3A4|
|• Mean half-life||Approximately nine days for non-obese patients|
|(approximately 16 days for obese patients)|
|• Protein binding||>99%|
|• Excretion||Approximately 3% in urine and about 86% in feces|
|(unchanged and metabolites)|
|Tmax = time to peak concentration; CYP = cytochrome.|
|From Electronic Medicines Compendium, 2006.|