Chapter 005. Principles of Clinical Pharmacology (Part 2)

Chia sẻ: Thuoc Thuoc | Ngày: | Loại File: PDF | Số trang:8

Thêm vào BST

Báo xấu

110
lượt xem 7
download

Download Vui lòng tải xuống để xem tài liệu đầy đủ

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. Absorption Bioavailability When 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 by other routes is termed bioavailability. Bioavailability may be ...

Chủ đề:

Bình luận(0) Đăng nhập để gửi bình luận!

Lưu

Nội dung Text: 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 drug delivered 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 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 by
other routes is termed bioavailability. Bioavailability may be
metabolism or excretion into the bile. This elimination in intestine and liver, which reduces the amount of drug delivered to the systemic circulation, is termed presystemic elimination, or first-pass elimination. Drug movement across the membrane of any cell, including enterocytes and hepatocytes, is a combination of passive diffusion and active transport, mediated by specific drug uptake and efflux molecules. The drug transport molecule that has been most widely studied is P-glycoprotein, the product of the normal expression of the MDR1 gene. P-glycoprotein is expressed on the apical aspect 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 to the systemic circulation. P-glycoprotein is also an important component of the blood-brain barrier, discussed further below. Drug metabolism generates compounds that are usually more polar and hence more readily excreted than parent drug. Metabolism takes place predominantly in the liver but can occur at other sites such as kidney, intestinal epithelium, lung, and plasma. "Phase I" metabolism involves chemical modification, most often oxidation accomplished by members of the cytochrome P450 (CYP) monooxygenase superfamily. CYPs that are especially important for drug metabolism (Table 5-1) include CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP1A2, and CYP2E1, and each drug may be a substrate for one or more of these enzymes. "Phase II" metabolism involves conjugation of specific
endogenous compounds to drugs or their metabolites. The enzymes that accomplish phase II reactions include glucuronyl-, acetyl-, sulfo- and methyltransferases. 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, ritonavir CYP2D6b 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 sulfonamides UGT1A1b Irinotecan Pseudocholinesteraseb Succinylcholine P-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 at http://medicine.iupui.edu/flockhart/table.htm.