Chapter 005. Principles of Clinical Pharmacology (Part 2)

Principles of Pharmacokinetics The processes of absorption, distribution, metabolism, and excretion— collectively termed drug disposition—determine the concentration of drug delivered to target effector molecules.AbsorptionBioavailabilityWhen a drug is administered orally, subcutaneously, intramuscularly, rectally, sublingually, or directly into desired sites of action, the amount of drug actually entering the systemic circulation may be less than with the intravenous route (Fig. 5-2A ). The fraction of drug available to the systemic circulation byother routes is termed bioavailability. Bioavailability may be ...
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Chapter 005. Principles of Clinical Pharmacology (Part 2) Chapter 005. Principles of Clinical Pharmacology (Part 2) Principles of Pharmacokinetics The processes of absorption, distribution, metabolism, and excretion—collectively termed drug disposition—determine the concentration of drugdelivered to target effector molecules. Absorption Bioavailability When a drug is administered orally, subcutaneously, intramuscularly,rectally, sublingually, or directly into desired sites of action, the amount of drugactually entering the systemic circulation may be less than with the intravenousroute (Fig. 5-2A ). The fraction of drug available to the systemic circulation byother routes is termed bioavailability. Bioavailability may be metabolism or excretion into the bile. This elimination in intestine and liver, whichreduces the amount of drug delivered to the systemic circulation, is termedpresystemic elimination, or first-pass elimination. Drug movement across the membrane of any cell, including enterocytesand hepatocytes, is a combination of passive diffusion and active transport,mediated by specific drug uptake and efflux molecules. The drug transportmolecule that has been most widely studied is P-glycoprotein, the product of thenormal expression of the MDR1 gene. P-glycoprotein is expressed on the apicalaspect of the enterocyte and on the canalicular aspect of the hepatocyte (Fig. 5-3);in both locations, it serves as an efflux pump, thus limiting availability of drug tothe systemic circulation. P-glycoprotein is also an important component of theblood-brain barrier, discussed further below. Drug metabolism generates compounds that are usually more polar andhence more readily excreted than parent drug. Metabolism takes placepredominantly in the liver but can occur at other sites such as kidney, intestinalepithelium, lung, and plasma. Phase I metabolism involves chemicalmodification, most often oxidation accomplished by members of the cytochromeP450 (CYP) monooxygenase superfamily. CYPs that are especially important fordrug metabolism (Table 5-1) include CYP3A4, CYP3A5, CYP2D6, CYP2C9,CYP2C19, CYP1A2, and CYP2E1, and each drug may be a substrate for one ormore of these enzymes. Phase II metabolism involves conjugation of specificendogenous compounds to drugs or their metabolites. The enzymes thataccomplish phase II reactions include glucuronyl-, acetyl-, sulfo- andmethyltransferases. Drug metabolites may exert important pharmacologic activity,as discussed further below. Table 5-1 Molecular Pathways Mediating Drug Disposition Molecule Substratesa Inhibitorsa CYP3A Calcium channel Amiodarone blockers Antiarrhythmics Ketoconazole, (lidocaine, quinidine, itraconazole mexiletine) HMG-CoA Erythromycin, reductase inhibitors clarithromycin (statins; see text) Cyclosporine, Ritonavir tacrolimus Indinavir, saquinavir, ritonavirCYP2D6b Timolol, Quinidine (even metoprolol, carvedilol at ultra-low doses) Phenformin Tricyclic antidepressants Codeine Fluoxetine, paroxetine Propafenone, flecainide Tricyclic antidepressants Fluoxetine, paroxetine CYP2C9b Warfarin Amiodarone Phenytoin Fluconazole Glipizide Phenytoin Losartan CYP2C19b Omeprazole Mephenytoin Thiopurine S- 6-Mercaptopurine,methyltransferaseb azathioprine N-acetyltransferaseb Isoniazid Procainamide Hydralazine Some sulfonamidesUGT1A1b IrinotecanPseudocholinesteraseb SuccinylcholineP-glycoprotein Digoxin Quinidine HIV protease Amiodarone inhibitors Many CYP3A Verapamil substrates Cyclosporine Itraconazole Erythromycin a Inhibitors affect the molecular pathway, and thus may affect substrate. b Clinically important genetics variants described. A listing of CYP substrates, inhibitors, and inducers is maintained athttp://medicine.iupui.edu/flockhart/table.htm.