Mechanism of action<unk>  is a prodrug, which is activated in two steps, first by the enzymes CYP2C19, CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. The active metabolite then specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin. Platelet inhibition can be demonstrated two hours after a single dose of oral<unk> , but the onset of action is slow, so a loading dose of either 600 or 300 mg is administered when a rapid effect is needed. Pharmacokinetics and metabolism<unk>  (top left) being activated: The first step is an oxidation mediated (mainly) by the enzyme CYP2C19, unlike the activation of the related drug prasugrel. The two structures at the bottom are tautomers of each other; and the final step is a hydrolysis. The active metabolite (top right) has Z configuration at the double bond C3–C16 and possibly R configuration at the newly asymmetric C4. After repeated oral doses of 75 mg of<unk>  (base), plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low and, in general, are below the quantification limit (0.258 µg/l) beyond two hours after dosing.<unk>  is activated in the liver by cytochrome P450 enzymes, including CYP2C19. Due to opening of the thiophene ring, the chemical structure of the active metabolite has three sites that are stereochemically relevant, making a total of eight possible isomers. These are: a stereocentre at C4 (attached to the —SH thiol group), a double bond at C3—C16, and the original stereocentre at C7. Only one of the eight structures is an active antiplatelet drug. This has the following configuration: Z configuration at the C3—C16 double bond, the original S configuration at C7, and, although the stereocentre at C4 cannot be directly determined, as the thiol group is too reactive, work with the active metabolite of the related drug prasugrel suggests the R-configuration of the C4 group is critical for P2Y12 and platelet-inhibitory activity. The active metabolite has an elimination half-life of about 0.5 to 1.0 h, and acts by forming a disulfide bridge with the platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to 3.5 times more likely to die or have complications than patients with the high-functioning allele. Following an oral dose of 14C-labeled<unk>  in humans, about 50% was excreted in the urine and 46% in the feces in the five days after dosing. * Effect of food: Administration of<unk>  bisulfate with meals did not significantly modify the bioavailability of<unk>  as assessed by the pharmacokinetics of the main circulating metabolite. * Absorption and distribution:<unk>  is rapidly absorbed after oral administration of repeated doses of 75-milligram<unk>  (base), with peak plasma levels (about 3 mg/l) of the main circulating metabolite occurring around one hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of<unk> . Absorption is at least 50% based on urinary excretion of<unk> -related metabolites.<unk>  and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is not saturable in vitro up to a concentration of 110 μg/ml. * Metabolism and elimination: In vitro and in vivo,<unk>  undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed. In March 2010, the U.S. Food and Drug Administration (FDA) added a boxed warning to Plavix alerting that the drug can be less effective in people unable to metabolize the drug to convert it to its active form. Pharmacogenetics CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs, including antidepressants, barbiturates, proton-pump inhibitors, and antimalarial and antitumor drugs.<unk>  is one of the drugs metabolized by this enzyme. In March 2010, the U.S. Food and Drug Administration (FDA) put a black box warning on Plavix to make patients and healthcare providers aware that CYP2C19-poor metabolizers, representing up to 14% of patients, are at high risk of treatment failure and that testing is available. Patients with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of the active metabolite of<unk> , less inhibition of platelets, and a 3.58-times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. A published review showed that some mutations of CYP2C19, CYP3A4, CYP2C9, CYP2B6, and CYP1A2 genes could affect the clinical efficacy and safety of<unk>  treatment. For instance, patients carrying the mutations CYP2C19*2, CYP2C19*3, CYP2C9*2, CYP2C9*3, and CYP2B6*5 alleles may not respond to<unk>  due to poor platelet inhibition efficacy revealed among them.
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