Pharmacokinetic Interactions Causing Decreased Drug Effects Gastrointestinal 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. John's wort, and glutethimide and by smoking, exposure to chlorinated insecticides such as DDT (CYP1A2),. | Chapter 005. Principles of Clinical Pharmacology Part 11 Pharmacokinetic Interactions Causing Decreased Drug Effects Gastrointestinal 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 H2 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. John s wort and glutethimide and by smoking exposure to chlorinated insecticides such as DDT CYP1A2 and chronic alcohol ingestion. Administration of inducing agents lowers plasma levels over 2-3 weeks as gene expression is increased. If a drug dose is stabilized in the presence of an inducer that is subsequently stopped major toxicity can occur as clearance returns to preinduction levels and drug concentrations rise. Individuals vary in the extent to which drug metabolism can be induced likely through genetic mechanisms. Interactions that inhibit the bioactivation of prodrugs will similarly decrease drug effects. The analgesic effect of codeine depends on its metabolism to morphine via CYP2D6. Thus the CYP2D6 inhibitor quinidine reduces the analgesic efficacy of codeine in EMs. Interactions that decrease drug delivery to intracellular sites of action can decrease drug effects tricyclic antidepressants can blunt the antihypertensive effect of clonidine by decreasing its uptake into adrenergic neurons. Reduced CNS penetration of multiple HIV protease inhibitors with the attendant risk of facilitating viral replication in a sanctuary site appears attributable to P-glycoprotein-mediated exclusion of the drug from the CNS indeed inhibition of P-glycoprotein has been proposed as a therapeutic approach to enhance drug entry to
