Chapter 005. Principles of Clinical Pharmacology (Part 11)

Pharmacokinetic Interactions Causing Decreased Drug EffectsGastrointestinal absorption can be reduced if a drug interaction results in drug binding in the gut, as with aluminum-containing antacids, kaolin-pectin suspensions, or bile acid sequestrants. Drugs such as histamine H 2 receptor antagonists or proton pump inhibitors that alter gastric pH may decrease the solubility and hence absorption of weak bases such as ketoconazole.Expression of some genes responsible for drug elimination, notably CYP3A and MDR1, can be markedly increased by "inducing" drugs, such as rifampin, carbamazepine, phenytoin, St. Johns wort, and glutethimide and by smoking, exposure to chlorinated insecticides such as DDT (CYP1A2),...
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Chapter 005. Principles of Clinical Pharmacology (Part 11) Chapter 005. Principles of Clinical Pharmacology (Part 11) Pharmacokinetic Interactions Causing Decreased Drug Effects Gastrointestinal absorption can be reduced if a drug interaction results indrug binding in the gut, as with aluminum-containing antacids, kaolin-pectinsuspensions, or bile acid sequestrants. Drugs such as histamine H 2 receptorantagonists or proton pump inhibitors that alter gastric pH may decrease thesolubility and hence absorption of weak bases such as ketoconazole. Expression of some genes responsible for drug elimination, notably CYP3Aand MDR1, can be markedly increased by inducing drugs, such as rifampin,carbamazepine, phenytoin, St. Johns wort, and glutethimide and by smoking,exposure to chlorinated insecticides such as DDT (CYP1A2), and chronic alcoholingestion. Administration of inducing agents lowers plasma levels over 2–3 weeksas gene expression is increased. If a drug dose is stabilized in the presence of aninducer that is subsequently stopped, major toxicity can occur as clearance returnsto preinduction levels and drug concentrations rise. Individuals vary in the extentto which drug metabolism can be induced, likely through genetic mechanisms. Interactions that inhibit the bioactivation of prodrugs will similarlydecrease drug effects. The analgesic effect of codeine depends on its metabolismto morphine via CYP2D6. Thus, the CYP2D6 inhibitor quinidine reduces theanalgesic efficacy of codeine in EMs. Interactions that decrease drug delivery to intracellular sites of action candecrease drug effects: tricyclic antidepressants can blunt the antihypertensiveeffect of clonidine by decreasing its uptake into adrenergic neurons. Reduced CNSpenetration of multiple HIV protease inhibitors (with the attendant risk offacilitating viral replication in a sanctuary site) appears attributable to P-glycoprotein-mediated exclusion of the drug from the CNS; indeed, inhibition ofP-glycoprotein has been proposed as a therapeutic approach to enhance drug entryto the CNS (Fig. 5-5A ). Pharmacokinetic Interactions Causing Increased Drug Effects The most common mechanism here is inhibition of drug elimination. Incontrast to induction, new protein synthesis is not involved, and the effectdevelops as drug and any inhibitor metabolites accumulate (a function of theirelimination half-lives). Since shared substrates of a single enzyme can compete foraccess to the active site of the protein, many CYP substrates can also beconsidered inhibitors. However, some drugs are especially potent as inhibitors(and occasionally may not even be substrates) of specific drug-eliminationpathways, and so it is in the use of these agents that clinicians must be most alertto the potential for interactions (Table 5-2). Commonly implicated interactingdrugs of this type include cimetidine, erythromycin and some other macrolideantibiotics (clarithromycin but not azithromycin), ketoconazole and other azoleantifungals, the antiretroviral agent ritonavir, and high concentrations of grapefruitjuice (Table 5-2). The consequences of such interactions will depend on the drugwhose elimination is being inhibited; high-risk drugs are those for which alternatepathways of elimination are not available and for which drug accumulationincreases the risk of serious toxicity (see The Concept of High-RiskPharmacokinetics, above). Examples include CYP3A inhibitors increasing therisk of cyclosporine toxicity or of rhabdomyolysis with some HMG-CoAreductase inhibitors (lovastatin, simvastatin, atorvastatin), and P-glycoproteininhibitors increasing risk of digoxin toxicity. Phenytoin, an inducer of many systems, including CYP3A, inhibitsCYP2C9. CYP2C9 metabolism of losartan to its active metabolite is inhibited byphenytoin, with potential loss of antihypertensive effect. The antiviral ritonavir is a very potent CYP3A4 inhibitor that has beenadded to anti-HIV regimens, not because of its antiviral effects but because itdecreases clearance, and hence increases efficacy, of other anti-HIV agents.Grapefruit (but not orange) juice inhibits CYP3A, especially at high doses;patients receiving drugs where even modest CYP3A inhibition may increase therisk of adverse effects (e.g., cyclosporine, some HMG-CoA reductase inhibitors)should therefore avoid grapefruit juice. CYP2D6 is markedly inhibited by quinidine, a number of neuroleptic drugs(chlorpromazine and haloperidol), and the SSRIs fluoxetine and paroxetine.Clinical consequences of fluoxetines interaction with CYP2D6 substrates may notbe apparent for weeks after the drug is started, because of its very long half-lifeand slow generation of a CYP2D6-inhibiting metabolite. 6-Mercaptopurine, the active metabolite of azathioprine, is metabolized notonly by TPMT but also by xanthine oxidase. When allopurinol, a potent inhibitorof xanthine oxidase, is administered with standard doses of azathioprine or 6-mercaptopurine, life-threatening toxicity (bone marrow suppression) can result. A number of drugs are secreted by the renal tubular transport systems fororganic anions. Inhibition of these systems can cause excessive drugaccumulation. Salicylate, for example, reduces the renal clearance ofmethotrexate, an interaction that may lead to methotrexate toxicity. Renal tubularsecretion contributes substantially to the elimination of penicillin, which can beinhibited (to increase its therapeutic effect) by probenecid. Similarly, inhibition ofthe tubular cation transport system by cimetidine decreases the renal clearance ofdofetilide and of procainamide and its active metabolite NAPA.