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Transcript
Chapter 1 Pharmacokinetics 药物代谢动力学 PK process in the body Kinetic processes Part A Pharmacokinetic Processes 1. Overview 2. Transport of Drug in the Body 3. Pharmacokinetic Processes of the Drug in the Body Overview A. aqueous B. lipid cell channels in the membranes intercellular junctions C. carriers (transporters) (into or out of cells) D. endocytosis exocytosis Mechanisms of drug permeation Part A Pharmacokinetic Processes 2. Transport of Drug in the Body 2.1 Transmembrane Transport of Drugs (1) Non-carrier transport Simple diffusion(简单扩散/单纯扩散) Filtration(滤过) Part A Pharmacokinetic Processes Characteristics of simple diffusion Not involving specific carriers Energy-independent No saturability No competition with other drugs Concentration gradient (down-hill) Part A Pharmacokinetic Processes (2) Carrier-mediated transport a. Active transport Characteristics of active transport Involving specific carrier (transporter) Energy-dependent Saturability Competition at same carrier Moving against concentration gradient (up-hill) Part A Pharmacokinetic Processes b. Facilitated diffusion(易化扩散) (transporter-mediated diffusion) Involving specific carriers (transporter) Energy-independent Saturability Competition with other drugs Concentration gradient (down-hill) (3) Membrane moving transport(膜动转运) Endocytosis/exocytosis(入胞/出胞) Part A Pharmacokinetic Processes A. Simple diffusion Most drugs are weak acids or bases. Their diffusion passing through cell membrane depends the lipid-soluble state (un-ionized form) Part A Pharmacokinetic Processes Determinants of simple diffusion For most drugs of small molecules (usually are weak acids or weak bases): Lipid-soluble or un-ionized forms pKa of the drug and pH of the body fluid The pKa is the pH at which the concentrations of the ionized and un-ionized forms are equal. Part A Pharmacokinetic Processes Henderson-Hasselbalch equation Weak acid drugs: pH - pKa = log ( [A-] / [HA] ) pKa - pH = log ( [HA] / [A-] ) Weak base drugs: pKa - pH = log ( [BH+] / [B] ) pH - pKa = log ( [B] / [BH+] ) Part A Pharmacokinetic Processes pH pKa Weak acids And / or Weak bases And / or And / or And / or un-ionized form lipidsoluble Simple diffusion Part A Pharmacokinetic Processes Implications Absorption: Stomach/intestine Distribution: Plasma/intracellular Excretion: Urine pH/weak acid or base Weak acid Weak base Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood B. Carrier (transporter)-mediated transport Three types of functional membrane proteins. Models of transmembrane transport across the lipid bilayer Transporter superfamily(转运体超家族) 根据不断增加的转运体成员,人类基因命名委员会对转运体作了标准化命 名,分为两大类: ATP-结合盒转运体(ATP-binding cassette [ABC] transporters)— mediating active transport 12次跨膜结构 (P-gp、MRP4、MRP5) 17次跨膜结构 (MRP1、MRP2、MRP3、MRP6) 6次跨膜结构 (BCRP, 组成二聚体发挥作用) 溶质载体转运体(solute carrier [SLC] transporters) — mediating facilitated diffusion 有机阴离子转运体(organic anion transporter, OAT)家族 有机阳离子转运体(organic cation transporter, OCT)家族 多肽转运体(peptide transporter, PEPT) 核苷转运体(nucleoside transporter, NT) Primary active transport (P-glycoprotein, multidrug resistance protein [MRP] ) Secondary active transport + facilitated diffusion (organic anion / caion transporters) Transporters of drugs in PK processes Part A Pharmacokinetic Processes 2.2 Free and Bound Forms Plasma protein binding Tissue / organ affinity Part A Pharmacokinetic Processes 3. Fate of the drug in the body Absorption Distribution Metabolism (Biotransformation) Excretion - ADME ADME Part A Pharmacokinetic Processes 3.1 Absorption Absorption is the transfer of a drug from its site of administration to the blood stream. Gastrointestinal tract Parenteral injection - i.m., s.c. Inhalation Transdermal Part A Pharmacokinetic Processes (1) Gastrointestinal tract Route: Oral Sublingual Rectal Absorption sites: Oral Gastric Intestinal Rectal Part A Pharmacokinetic Processes Factors influencing absorption: blood flow to the absorption site total surface area available for absorption contact time at the absorption surface physic-chemical properties of the drug first-pass elimination Part A Pharmacokinetic Processes First-pass elimination(首过消除) When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver or intestinal mucosa, the amount of unchanged drug that gains access to the systemic circulation is decreased. Part A Pharmacokinetic Processes (2) Parenteral injection intramuscular injection ( i.m. ) subcutaneous injection ( s.c. ) Determinants Local blood flow Solubility of the drug Part A Pharmacokinetic Processes (3) Others Inhalation Transdermal Intranasal Topical Part A Pharmacokinetic Processes 3.2 Distribution Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. Blood flow-dependent phase of distribution Selective distribution Tissue-plasma balance: importance of measuring plasma concentration Body fluid volume: Sites of drug distribution Part A Pharmacokinetic Processes (1) Binding of drug to plasma proteins Bound drug: can not distribute / inactive temporally reversible (storage form)/ percentage of binding plasma protein capacity competitive displacement Part A Pharmacokinetic Processes Competitive displacement Class I drugs: Dose less than available binding sites. Most drug molecules are bound to the proteins and free drug concentration is low. Class II drugs: Dose greater than available binding sites. Most proteins contain a bound drug and free drug concentration is significant. Class I + Class II drugs: Displacement of Class I drug occurs when a Class II drug is administered simultaneously. Example: Class I: Tolbutamide (甲苯磺丁脲) Class II: Sulfonamide (磺胺类药物) competitive displacement Part A Pharmacokinetic Processes (2) Physic-chemical properties of the drug (3) Blood flow and re-distribution (4) Affinity to organs or tissues (5) Barriers Blood-brain barrier (BBB) Placental barrier Blood-eye barrier Blood-brain barrier (BBB) Able to pass through Unable to pass through Small molecules Large molecules Lipid-soluble Water-soluble Transporter-mediation Part A Pharmacokinetic Processes Amount of drug passing through bloodbrain barrier Percentage of drug in c.s.f. Increases when Inflammation Larger doses used BBB permeability increases in inflammation Placental barrier: More permeable Drugs for pregnant women: A, B – relatively safe C - caution D, X - toxic Part A Pharmacokinetic Processes 3.3 Metabolism (biotransformation) Drug metabolism is the process transforming lipophilic drug into more hydrophilic metabolites, which is essential for the elimination of these compounds from the body and termination of their biological activity. (1) Metabolism sites Liver: for most of the drugs Other organs/tissues: intestine, kidney, lung, plasma, etc. Part A Pharmacokinetic Processes (2) Phases of metabolism Phase I: Oxidation, reduction, most drugs are inactivated few (prodrugs) is activated Phase II: Conjugation inactivated hydrolysis Metabolites: more water-soluble easier to excrete Part A Pharmacokinetic Processes Part A Pharmacokinetic Processes (3) Enzymes in drug metabolism Enzymes in Phase I: cytochrome-P450 many other enzymes Enzymes in Phase II: acetylase glucuronosyltransferase etc. Superfamily of cytochrome-P450 CYP2A6(cytochrome-P450 / family / subfamily / member) Part A Pharmacokinetic Processes (4) Properties of drug metabolism enzymes a. Lower selectivity to substrates b. Larger individual variability c. Induction and inhibition determinants (including drugs) by environmental Rapid acetylation Slow acetylation Individual variability of isoniazid metabolism Part A Pharmacokinetic Processes Induction of hepatic enzymes by drugs example: phenytoin-steroids, nifedipine Inhibition of hepatic enzymes by drugs example: verapamil-diazepam 肝药酶诱导剂对双香豆素血浓度及凝血作用的影响 Part A Pharmacokinetic Processes 3.4 Excretion Removal of a drug from the body via a number of routes. Elimination of drugs from the body Action on excretory organs Part A Pharmacokinetic Processes 3.4 Excretion (1) Excretion routes Kidney Bile Lung GI tract Milk Secretion glands Part A Pharmacokinetic Processes (2) Renal excretion Glomerular filtrattion renal blood flow Active tubule secretion specific carriers / competition Passive tubule reabsorption urine pH, urine flow Part A Pharmacokinetic Processes (3) Bile excretion Carrier-mediated active transport Hepato-enteral circulation Part A Pharmacokinetic Processes 3.5 Elimination and Accumulation Elimination(消除): Metabolism Excretion Distribution (stored in fat, hair, etc) Accumulation(蓄积): Dosing rate > elimination rate