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Fig. 6.10. CYP450 Drug-Drug Interaction Probes

Inhibition or induction of an interacting drug may or may not result in a clinically significant interaction. Drug(s) may induce/inhibit one isoenzyme but may not be a substrate of it (quinidine is an inhibitor of CYP2D6 but a substrate of CYP3A4). Drug-drug interactions (DDI) can be of following types: inhibition or induction. Inhibition is the more common form of DDI.

• Enzyme inhibition: Decreased enzyme activity due to direct interaction with the drug or its metabolite(s)

£ Competitive inhibition: Inhibitor and the substrate compete for the same binding site on an enzyme. Inhibitor may be the substrate itself. £ Noncompetitive inhibition: Inhibitor binds at a site on the enzyme distinct from the substrate. £ Uncompetitive inhibition: Inhibitor binds only to the enzyme substrate complex. £ Mechanism-based (or suicide) inhibition: Substrate (inhibitor) gets transformed by the enzyme to intermedi-ate(s), which can react with the active site of the enzyme or inactivate the enzyme.

• Enzyme induction: Interaction may affect efficacy of one or more medications. Enzyme induction involves protein synthesis, therefore, requires multiple dose administration to realize.

Many phase I and phase II enzymes are inducible (e.g., CPY3A4, UDP-glucuronosyltransferases), but some are not (CYP2D6). The major enzyme that is known to be induced is CYP3A, and examples of drugs known to induce CYP3A include carbamazepine, phenytoin, rifampin, and phenobarbital. Enzyme induction potential in human is difficult to assess preclinically due to lacking of predictability of animal data.

Absorption, interaction with transporter (e.g., P-gp), elimination, and protein binding based drug-drug interactions are also possible, but they are more infrequent or less well studied.

Drug metabolism and interaction studies are usually realized using appropriate probes [4, 5]. These probes, which are drugs with known actions, are classified as substrates, inducers, and inhibitors of various drug metabolizing enzymes or transporters (Fig. 6.10). For in vivo studies, selectivity, sensitivity, safety, and availability of the probe compounds are the major factors to be considered. For in vitro tests, the choices are a little more broad: if recombinant enzymes (isoenzyme specific) are used, the probes can be less selective. Human liver microsomes are preferred in the in vitro tests. Via the probe approach, an NCE's metabolic pathways and its interaction potential can be assessed in vitro initially and ultimately confirmed clinically via human DDI studies. The results gathered are critical in the decision-making in drug discovery and development. An NCE that is subjected to drug interactions as a strong inducer or as substrate that is primarily metabolized by a single enzyme (e.g., CYP2D6 or 3A) may be screened out early (development stopped) because drug interactions likely will be common and significant, as long there are other similar leads with more diverse metabolic profiles (i.e., metabolized by multiple metabolic and other elimination pathways). Other types of drug-drug interactions involving non-CYP enzymes (e.g., flavin monooxygenases; FMO), drug-transporters, protein binding, or absorption and elimination related are also possible. MDR1 (P-glycoprotein) is an efflux transporter that can actively extrude or pump drugs back into the intestinal lumen, thus affecting the oral bioavailability of drugs such as paclitaxel, digoxin, and protease inhibitors [6].

When elimination occurs via a single metabolic pathway, individual differences in metabolic rates based on pharmacogenomics can lead to large differences in drug and metabolite concentrations in the blood and tissue. Figure 6.11 presents several CYP450 isozymes responsible for metabolism of drugs along with the proportion of drugs metabolized by particular CYP isozyme, the allele variants, and the clinical impact [7]. In some instances, differences exhibit a bimodal distribution indicative of a genetic polymorphism for the metabolic enzyme (e.g., CYP450 2D6, CYP450 2C19, ^-acetyl transferase). When a genetic polymorphism affects an important metabolic route of elimination, large dosing adjustments between patients may be necessary to

Fig. 6.11. Pharmacogenetics & Pharmacogenomics

Source: Influences on Pharmacologic Responses. http://medicine.iupui.edu/flockhardt/

Enzyme

% of Drug Metabolism

Allele Variantsb

Clinical Effects

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