Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

https://journal.chestnet.org/article/S0012-3692(12)60121-4/pdf

Antiplatelet Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, biva- lirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and trig- gering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteo- porosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fonda- parinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fonda- parinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bio- availability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fidoses, without coagulation monitoring. Three addi- tional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to hep- arin in patients with HIT.

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Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA). Knowledge of the CYP-dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the pharmacokinetics of and pharmacodynamic response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to thienopyridine antiplatelet therapy with prasugrel. Current literature shows that greater ADP-mediated IPA is associated with significantly better clinical outcomes for patients with acute coronary syndrome.

Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans.

Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y(12) ADP receptor. In this open-label, 4-period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. C(max) and AUC(0-tlast) of prasugrel's active metabolite, R-138727, and clopidogrel's inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R-138727 AUC(0-tlast) and C(max) by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.

Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel

Prasugrel, a prodrug, is a novel and potent inhibitor of platelet aggregation in vivo. The metabolism of prasugrel and the elimination and pharmacokinetics of its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), three inactive metabolites, and radioactivity were determined in five healthy male subjects after a single 15-mg (100 microCi) p.o. dose of [(14)C]prasugrel. Prasugrel was rapidly absorbed, and maximum plasma concentrations of radioactivity and R-138727 were achieved in 30 min, indicating rapid formation of R-138727. Prasugrel was extensively metabolized in humans, first by hydrolysis to a thiolactone, followed by ring opening to form R-138727, which was further metabolized by S-methylation and conjugation with cysteine. Total radioactivity was higher in plasma than in blood, suggesting limited penetration of prasugrel metabolites into red blood cells. Approximately 70% of the dose was excreted in the urine and 25% in the feces.

https://dmd.aspetjournals.org/content/dmd/early/2007/04/02/dmd.106.014522.full.pdf

The disposition of prasugrel, a novel thienopyridine, in humans.

Disposition and metabolism of isoeugenol in the male Fischer 344 rat.

trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a b-unsaturated ketone that has a wide range of uses in industry, as well as consumer products. MSK does not appear to be overtly toxic in animal models, however, it has been shown to be mutagenic in several in vitro assays after S-9 activation. In this study experiments were conducted to characterize MSK absorption, distribution, metabolism, and elimination after iv, oral, and topical administration to female B6C3F1 mice. After iv administration, [ 14 C]MSK (20 mg/kg; 120 mCi/kg) was rapidly cleared from the blood as evidenced by the following pharmacokinetic values (mean 6 SD): terminal disposition half-life (t1⁄2), 7.98 6 1.72 min; mean residence time, 5.6 6 1.7 min; steady-state apparent volume of distribution (Vss), 3.33 6 0.75 liters/kg; and systemic body clearance (CLs), 0.53 6 0.05 liters/min/kg. Within 48 hr, 92.4% of the dose was excreted in the urine and 3.5% in the feces. The major blood metabolites after iv administration were identified by GC-MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol), 4-hydroxy-4phenyl-2-butanone, and benzyl alcohol. After oral administration of [ 14 C]MSK (200 mg/kg; 100 mCi/kg), 95% of the dosed radioactivity was recovered in the urine and 1.2% in the feces within 48 hr. Major urinary metabolites were identified by LC-MS/MS as N-phenylacetyl-l-glycine (35.1% of dose) and N-benzyl-L-glycine (19.1% of dose). Only a small amount of MSK was detected in the blood after oral administration (;0.73 mg/ml at 10 min), and [ 14 C]-equivalents in the blood never exceeded 2.8% of the dose. Ater topical application of [ 14 C]MSK (250 mg/kg; 50 mCi/kg), approximately 40% of the dose was absorbed and 84.5% of the absorbed dose was excreted into the urine (36% of the total dose). Urinary metabolites were similar to those described for oral administration. Importantly, [ 14 C]-equivalents were not detected in the blood at any time after dermal administration. These results indicate that the rate of MSK clearance is equivalent to its rate of absorption, and tissue exposure to intact MSK is expected to be limited.

Absorption, disposition, and metabolism of trans-methyl styryl ketone in female B6C3F1 mice.

3,39,4,49-Tetrachloroazoxybenzene (TCAOB) is a structural analog of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It is formed as a byproduct during the synthesis of industrial products such as herbicides. TCAOB is a ligand for the Ah receptor and, at much higher doses, exhibits toxicities similar to TCDD. Although the reduced in vivo toxicity of TCAOB probably reflects differences in disposition, this study characterized its absorption and disposition kinetics. Male Fischer 344 rats were administered [14C]TCAOB (3.4 or 34 mg/kg p.o., 3.4 mg/kg i.v.), and the excretion of the radiolabel was monitored over 96 hr. After the low and high dose, 35% and 30% of the [14C]TCAOB were eliminated in the urine, with 55% and 54% eliminated in the feces. At 96 hr, the adipose tissue:blood ratios of [14C]TCAOB equivalents were 8 and 26 for the low and high doses, respectively. After the intravenous dose of TCAOB, the adipose tissue:blood ratio was 21 at 96 hr. Other tissue:blood ratios were of little significance (0.06-3.2). Pharmacokinetic parameters indicate that the parent molecule is cleared from blood with an average half-life of 7 hr and an average clearance of 11 ml/min.kg. Absolute bioavailability was calculated to be approximately 9%. Urine contained a variety of dichlorolaniline conjugates, which support the importance of azo reduction in the disposition of TCAOB. When compared with TCDD, the absorption of TCAOB is greatly reduced and the elimination of metabolites greatly enhanced. Therefore, at equal molar oral doses, TCAOB would express lower levels of Ah receptor-mediated toxicity than those defined for TCDD.

R L Smith

Papers

The disposition of prasugrel, a novel thienopyridine, in humans.

Disposition and metabolism of isoeugenol in the male Fischer 344 rat.

Absorption, disposition, and metabolism of trans-methyl styryl ketone in female B6C3F1 mice.

Absorption and disposition kinetics of 3,3',4,4'-tetrachloroazoxybenzene in the male Fischer 344 rat.

Simultaneous determination of cyclohexene oxide and its metabolites in rat plasma and urine by gas chromatography