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Additional resources for Cardiovascular Pharmacotherapeutics (3rd Edition)
Lipoproteins also bind some lipophilic and basic compounds. , but these are of little consequence for drugs and other xenobiotics. Binding to plasma proteins is always reversible, and the half-time of binding and release is exceedingly short (measured in milliseconds). Thus, even in the case of extensive (tight) binding, it is rapidly reversible under physiologic conditions. Since concentration gradients, which determine the rate of passive transport across membranes, are based solely on free drug, it follows that binding to plasma proteins slows the rate of removal of a drug from plasma by diminishing the concentration gradient across capillary cell membranes.
Hepatic extraction is sensitive to plasma protein binding. For low-extraction drugs, binding is of considerable importance, whereas hepatic uptake of high extraction drugs is little influenced by binding. Displacement of drugs from binding sites increases the proportion of free drug in the plasma and thus the effective concentration of the drug in extravascular compartments. Similarly, increasing the dose of a drug beyond binding capacity disproportionately increases the unbound fraction within the plasma and may lead to undesired pharmacologic effects.
Erythromycin and ketoconazole block the conversion of terfenadine, a prodrug, to its active metabolite. Since the parent compound is arrhythmogenic, serious cardiac toxicity may be seen with such drug combinations. For this reason, terfenadine was banned, although its active metabolite is marketed as fexofenadine (Allegra), which lacks cardiotoxicity and adverse CNS effects. It is suspected that there are many more such inhibitory drugs, 14 Cardiovascular Pharmacotherapeutics TABLE 1-3. Major Inhibitors and Substrates of Different Cytochrome P450 (CYP450) Enzymes CYP450 Enzymes Inhibitors Inducers CYP1A2 Cimetidine, ciprofloxacin, clarithromycin, erythromycin, fluvoxamine, grapefruit juice, isoniazid, ketoconazole, levofloxacin, paroxetine Phenobarbital, phenytoin, rifampin, ritonavir, smoking CYP2C9 Amiodarone, chloramphenicol, cimetidine, fluvoxamine, omeprazole, zafirlukast Carbamazepine, phenobarbital, phenytoin, rifampin CYP2D6 Amiodarone, cimetidine, desipramine, fluoxetine, fluphenazine, haloperidol, paroxetine, propafenone, quinidine, ritonavir, sertraline Carbamazepine, phenobarbital, phenytoin, rifampin, ritonavir CYP3A4 Carbamazepine, dexamethasone, ethosuximide, Amiodarone, clarithromycin, erythromycin, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, phenobarbital, phenytoin, rifabutin, rifampin, indinavir, itraconazole, ketoconazole, metronidazole, troglitazone nefazodone, ritonavir, saquinavir, sertraline, zafirlukast Reproduced with permission from Cheng JWM.