Drug Metabolism And Resistance

Drug metabolism is generally classified in two phases, the initial oxidation or reduction reactions termed Phase I and Phase II reactions that create more water soluble and easily excreted forms of the drugs.

Phase I reactions include oxidation or reduction reactions, usually through the actions of cytochrome P450 oxidative enzymes or reductases. These enzymes prepare fat-soluble molecules for further metabolism via Phase II reactions by creating a reactive group suitable for conjugation. Drug interactions are usually the result of interactions with Phase I drug metabolism mechanisms. Conjugation reactions performed during Phase II metabolism of drugs usually involve the addition of a peptide (glutathione), sugar, or sulfur group to the drug molecule. These groups are usually common and easily accessible in well-nourished cells, so these Phase II reactions are rarely rate-limiting, and therefore rarely involved in drug interactions.

Phase I reactions carried out by cytochrome P450 enzymes, flavin monooxygenases, and reductases are more frequently rate-limiting, and are more often the target of clinically significant drug interactions. Phase I oxidative enzymes are mostly found in the endoplasmic reticulum within liver cells. The main enzymes responsible for Phase I reactions involve the microsomal mixed function oxidation system. This system requires the presence of NADPH and NADPH-cytochrome P450 reductase (see Fig. 3.1). ''Cytochrome P450'' refers to a super-family of enzymes that comprise the terminal oxidase of this system. They form part of the cascade that shuttles electrons from molecular oxygen to oxidize drugs. Six cytochrome P450 (CYP) isoforms have been recognized as important in human drug metabolism: CYP1A2, CYP3A, CYP2C9, CYP2C10, and CYP2D6. Three of these isoforms—CYP2C9, CYP2C19, and CYP2D6—can be genetically absent. The enzyme-inducing AEDs (EIAEDs) are typically metabolized by CYP3A4, CYP2C9, and CYP2C19 [27]. Table 3.1 lists the specific CYP enzymes induced or inhibited by AEDs.

Advances in the understanding of the basic biology of the induction of drug metabolism provide a scientific scaffold for understanding drug interactions between EIAEDs and chemotherapeutics. The molecular mechanisms underlying induction and increased elimination of drugs from the body involve drug interactions with the nuclear receptor superfamily of ligand-activated transcription factors (ligands include drugs, hormones, nutrients, and metabolites) [28]. Several classes of nuclear receptors that mediate drug enzyme induction have been identified. In particular these include

(1) CAR or constitutive androstane receptor,

(2) PXR or pregnane X receptor,

(3) PPAR or peroxisome proliferators-activated receptor,

(4) AhR or aryl hydrocarbon receptor [29].

EIAEDs like phenobarbital and phenytoin actually led to the discovery of CAR, and this remains one of the best experimental models for studying drug induction [30]. CAR mediates the induction of CYP enzymes 2B6, 2C9, and 3A4, and in addition induces some drug conjugation enzymes responsible for Phase II reactions. Both the CAR and PXR receptors act as drug sensors that regulate an overlapping set of genes that increase oxidative drug metabolism,

Induction by EIAEDs CTA-H

Inhibition ^ V CTA-H

Induction by EIAEDs CTA-H

Inhibition ^ V CTA-H

FIGURE 3.1 Explaining the EIAED-CTA interaction.

Graphic depiction of the mechanism by which the EIAED-CTA interactions occur via the cytochrome P-450 enzyme system. P-450 enzymes metabolize CTAs via a variety of reactions, including dealkylation, hydroxy-lation, and oxidation (pictured).

FIGURE 3.1 Explaining the EIAED-CTA interaction.

Graphic depiction of the mechanism by which the EIAED-CTA interactions occur via the cytochrome P-450 enzyme system. P-450 enzymes metabolize CTAs via a variety of reactions, including dealkylation, hydroxy-lation, and oxidation (pictured).

Sequence:

1. Oxidized CYP-450 combines with CTA substrate to form a complex.

2. and 3. NADPH releases an electron to CYP-450-reductase. A second electron (from NADPH) reduces molecular oxygen to form "activated oxygen" CYP-450-CTA complex.

4. This complex transfers oxygen to the CTA molecule, rendering it water soluble for renal elimination, and (in most cases) inactive as a chemotherapeutic agent.

5. Coadministration of an EIAED induces increased P-450 enzyme production by activation of gene transcription resulting in increased P-450 enzyme production and decreased plasma concentrations of the CTA substrate. Valproic acid exerts the opposite effect, inhibiting P-450 metabolism, probably through competition.

conjugation, and transport. These genes include several CYPs, Phase II conjugation enzymes, multiple drug resistance-associated proteins (MRPs), and organic anion transporters (OATs) [31].

Phase II Metabolism

Phase II reactions conjugate a water soluble group to a drug in order to allow biliary or renal excretion. These Phase II enzymes include UDP-glucuronyl transferase (UGTs), sulfotransferases (SULTs), and glutathione S-transferases (GSTs), and also some drug transporter enzymes [32-34]. UGTs, SULTs, and GSTs prepare polar drugs for biliary or urinary excretion. Glucuronide conjugation is performed by the two main families, UGT1 and UGT2, each of which have several isoforms [35]. The activity of UGT enzymes varies within the human population, and low UGT enzyme activity can lead to severe toxicity of some CTAs such as irinotecan, which requires glucuronidation for inactivation [36]. SULT-mediated sulfation also plays an essential role in drug removal, and is performed by two major families, SULT1 and SULT2, which can be induced by phenobarbital via the CAR receptor [34]. GSTs are a family of enzymes that are also inducible by phenobarbital via the CAR receptor. They conjugate glutathione to a wide variety of drugs to inactivate them. Potential upregulation of the conjugation phase II enzymes for those CTAs affected by conjugation processes is a consideration with EIAED treatment, although this type of interaction is less frequent than interaction via the induction of CYP. A molecular understanding of EIAED effects can be useful in choosing specific EIAEDs and NEIAEDs in the clinical setting.

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