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Antibacterial agents

Hypersensitivity, hemolytic anemia,

fever, lupus-like syndromes fever, lupus-like syndromes to such drug-induced reactions. Thus, knowledge of a patient's acetylating phenotype can be important in avoiding drug toxicity.

Tissue-specific NAT expression can affect toxicity of environmental pollutants. NAT1 is ubiquitously expressed in human tissues, whereas NAT2 is found in liver and the GI tract. Both enzymes have a capacity to form N-hydroxy-acetylated metabolites from bicyclic aromatic hydrocarbons, a reaction that leads to the nonenzymatic release of the acetyl group and the generation of highly reactive nitrenium ions. Thus, N-hydroxy acetylation is thought to activate certain environmental toxicants. In contrast, direct N-acetylation of the environmentally generated bicyclic aromatic amines is stable and leads to detoxification. NAT2 fast acetylators efficiently metabolize and detoxify bicyclic aromatic amine through liver-dependent acetylation. Slow acetylators (NAT2 deficient) accumulate bicyclic aromatic amines, which are metabolized by CYPs to N-OH metabolites that are eliminated in the urine. In bladder epithelium, NAT1 efficiently catalyzes the N-hydroxy acetylation of bicyclic aromatic amines, a process that leads to deacetylation and the formation of the mutagenic nitrenium ion. Slow acetylators due to NAT2 deficiency are predisposed to bladder cancer if exposed to environmental bicyclic aromatic amines.

METHYLATION In humans, xenobiotics can undergo O-, N-, and S-methylation. Methyl-transferases (MTs) are identified by substrate and methyl conjugate. Humans express three N-methyltransferases, one catechol-O-methyltransferase (COMT), a phenol-O-methyltransferase (POMT), a thiopurine S-methyltransferase (TPMT), and a thiol methyltransferase (TMT). All MTs use S-adenosyl-methionine as the methyl donor. Except for a conserved signature sequence, there is limited overall sequence conservation among the MTs, indicating that each MT has evolved to display a unique catalytic function. Although all MTs generate methylated products, the substrate specificity of each is high.

Nicotinamide N-methyltransferase (NNMT) methylates serotonin, tryptophan, andpyridine-containing compounds such as nicotinamide and nicotine. Phenylethanolamine N-methyltransferase (PNMT)

is responsible for the methylation of norepinephrine to form epinephrine; the histamine N-methyltransferase (HNMT) metabolizes substances containing an imidazole ring (e.g., histamine). COMT methylates neurotransmitters containing a catechol moiety (e.g., dopamine and norepinephrine, methyldopa, and drugs of abuse such as ecstasy). The most important MT clinically may be TPMT, which catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including the thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine. AZA and 6-MP are used for inflammatory bowel disease (see Chapter 38) and autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. Thioguanine is used in acute myeloid leukemia, and 6-MP is used to treat childhood acute lymphoblastic leukemia (see Chapter 51). Because TPMTis responsible for the detoxification of 6-MP, a genetic deficiency in TPMT can result in severe toxicities in patients taking these drugs. The toxic side effects arise when a lack of 6-MP methylation by TPMT causes accumulation of 6-MP, resulting in the generation of toxic levels of 6-thioguanine nucleotides. Tests for TPMT activity have made it possible to identify individuals who are predisposed to the toxic side effects of 6-MP therapy, who therefore should receive a decreased dose.

INDUCTION OF DRUG METABOLISM Xenobiotics can influence the extent of drug metabolism by activating transcription and inducing the expression of genes encoding drug-metabolizing enzymes. Thus, a drug may induce its own metabolism. One potential consequence of this is a decrease in plasma drug concentration as the autoinduced metabolism of the drug exceeds the rate at which new drug enters the body, resulting in loss of efficacy. Ligands and the receptors through which they induce drug metabolism are shown in Table 3-4. Figure 3-5 shows the scheme by which a drug may interact with nuclear receptors to induce its own metabolism. A particular receptor, when activated by a ligand, can induce the transcription of a battery of target genes, including CYPs and drug transporters. Any drug that is a ligand for a receptor that induces CYPs and transporters could cause altered drug metabolism and drug interactions.

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor that induces expression of genes encoding CYP1A1 and CYP1A2, which metabolically activate chemical carcinogens, including environmental contaminants and carcinogens derived from food. Many of these substances are inert unless metabolized by CYPs. Induction of CYPs by AHR could result in an increase in the toxicity and carcinogenicity of these procarcinogens. For example, omepra-zole, a proton pump inhibitor used to treat ulcers (see Chapter 36), is an AHR ligand and can induce CYP1A1 and CYP1A2, possibly activating toxins/carcinogens.

Another induction mechanism involves members of the nuclear receptor superfamily. Many of these receptors were originally termed "orphan receptors" because they had no known endogenous ligands. The nuclear receptors relevant to drug metabolism and drug therapy include the pregnane X receptor (PXR), constitutive androstane receptor (CAR), and the per-oxisome proliferator activated receptor (PPAR). PXR is activated by a number of drugs, including antibiotics (rifampin and troleandomycin), Ca2+ channel blockers (nifedipine), statins (mevastatin), antidiabetic drugs (rosiglitazone), HIV protease inhibitors (ritonavir), and anticancer drugs (paclitaxel). Hyperforin, a component of St. John's wort, also activates PXR. This activation is thought to be the basis for the decreased efficacy of oral contraceptives in individuals taking St. John's wort: activated PXR induces CYP3A4, which can metabolize steroids found in oral contraceptives. PXR also induces the expression of genes encoding certain drug

Table 3-4

Nuclear Receptors that Induce Drug Metabolism

Receptor Ligands

Aryl hydrocarbon receptor (AHR) Constitutive androstane receptor (CAR) Pregnane X receptor (PXR) Farnesoid X receptor (FXR) Vitamin D receptor

Peroxisome proliferator activated receptor (PPAR) Retinoic acid receptor (RAR) Retinoid X receptor (RXR)

Omeprazole Phenobarbital Rifampin Bile acids Vitamin D Fibrates all-trans-Retinoic acid 9-cis-Retinoic acid

FIGURE 3-5 Induction of drug metabolism by nuclear receptor—mediated signal transduction. When a drug such as atorvastatin (Ligand) enters the cell, it can bind to a nuclear receptor such as the pregnane X receptor (PXR). PXR then forms a complex with the retinoid X receptor (RXR), binds to DNA upstream of target genes, recruits coactivator (which binds to the TATA box binding protein, TBP), and activates transcription. Among PXR target genes are CYP3A4, which can metabolize the atorvastatin and decrease its cellular concentration. Thus, atorvastatin induces its own metabolism, undergoing both ortho- and para-hydroxylation.

FIGURE 3-5 Induction of drug metabolism by nuclear receptor—mediated signal transduction. When a drug such as atorvastatin (Ligand) enters the cell, it can bind to a nuclear receptor such as the pregnane X receptor (PXR). PXR then forms a complex with the retinoid X receptor (RXR), binds to DNA upstream of target genes, recruits coactivator (which binds to the TATA box binding protein, TBP), and activates transcription. Among PXR target genes are CYP3A4, which can metabolize the atorvastatin and decrease its cellular concentration. Thus, atorvastatin induces its own metabolism, undergoing both ortho- and para-hydroxylation.

transporters and phase 2 enzymes including SULTs and UGTs. Thus, PXR facilitates the metabolism and elimination of xenobiotics, including drugs, with notable consequences (see legend to Figure 3-5).

The nuclear receptor CAR was discovered based on its capacity to activate genes in the absence of ligand. Steroids such as androstanol, the antifungal agent clotrimazole, and the antiemetic meclizine are inverse agonists that inhibit gene activation by CAR, while the pesticide 1,4-bis (2-[3,5-dichloropyridyloxy]) benzene, the steroid 53-pregnane-3,20-dione, and probably other endogenous compounds are agonists that activate gene expression when bound to CAR. Genes induced by CAR include those encoding CYP2B6, CYP2C9, and CYP3A4, various phase 2 enzymes (including GSTs, UGTs, and SULTs), and drug and endobiotic transporters. CYP3A4 is induced by both PXR and CAR; thus, its level is highly influenced by a number of drugs and other xenobiotics. In addition to a potential role in inducing drug degradation, CAR may function in the control of bilirubin degradation, the process by which the liver decomposes heme. As with the xenobiotic-metabolizing enzymes, species differences also exist in the ligand specificities of these nuclear receptors. For example, rifampin activates human PXR but not mouse or rat PXR, while meclizine preferentially activates mouse CAR but inhibits gene induction by human CAR.

The PPAR family has three members, a, and g. PPARa is the target for the fibrate hyper-lipidemic drugs (e.g., gemfibrozil and fenofibrate). While PPARa activation induces target genes encoding fatty acid metabolizing enzymes that lower serum triglycerides, it also induces CYP4 enzymes that carry out the oxidation of fatty acids and drugs with fatty acid-containing side chains, such as leukotrienes and arachidonic acid analogs.

DRUG METABOLISM, DRUG DEVELOPMENT, AND THE SAFE AND EFFECTIVE USE OF DRUGS Drug metabolism influences drug efficacy and safety. A substantial percentage (~50%) of drugs associated with adverse responses are metabolized by xenobiotic-metabolizing enzymes, notably the CYPs. Many of these CYPs are subject both to induction and inhibition by drugs, dietary factors, and other environmental agents. This can result in decreases in drug efficacy and half life; conversely, changes in CYP activity can result in drug accumulation to toxic levels. Thus, before a new drug application is filed with the FDA, the routes of metabolism and the enzymes involved in this metabolism must be established, so that relevant polymorphisms of metabolic enzymes are identified and potential drug interactions can be predicted and avoided.

Historically, drug candidates have been administered to rodents at doses well above the human target dose in order to predict acute toxicity. For drug candidates that will be used chronically in humans, long-term carcinogenicity studies are carried out in rodent models. For determination of metabolism, the compound is subjected to interaction with human liver cells or extracts from these cells that contain the drug-metabolizing enzymes. Such studies determine how humans will metabolize a particular drug, and to a limited extent, predict its rate of metabolism. If a CYP is involved, a panel of recombinant CYPs can be used to determine which CYP predominates in the metabolism of the drug. If a single CYP, such as CYP3A4, is found to be the sole CYP that metabolizes a drug candidate, then a decision can be made about the likelihood of drug interactions. Interactions arise when multiple drugs are simultaneously administered, for example in elderly patients, who on a daily basis may take prescribed anti-inflammatory drugs, cholesterol-lowering drugs, blood pressure medications, a gastric-acid suppressant, an anticoagulant, and a number of over-the-counter medications. Ideally, a candidate drug would be metabolized by several CYPs, so that variability in expression levels of one CYP or drug-drug interactions would not significantly impact its overall metabolism and pharmacokinetics.

Similar studies can be carried out with phase 2 enzymes and drug transporters in order to predict the metabolic fate of a drug. In addition to the use of recombinant human xenobiotic-metabolizing enzymes in predicting drug metabolism, human receptor—based (PXR and CAR) systems should also be used to determine whether a particular drug candidate could be a ligand for PXR, CAR, or PPARa.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at

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