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Transcript
Review of Pharmacokinetics Jean D. Deupree, Ph.D. Department of Pharmacology University Nebraska Medical Center 3014 DRC 559-4565 [email protected] Helpful Hints • Be able to use the equations on p. 40-41. – Equations will not be provided on the exam – You will not be allowed to use a calculator on the exam • Be able to use the pharmacokinetic terms which have been defined • Be able to calculate the ionization of acid and bases in various biological media • Understand the different types of drug-drug interactions that can occur • Be able to apply the information. Exam question are not likely to be asked in the same manner as in this review • When reviewing old exams make sure you understand why the wrong answers are wrong and the right answers are right 2 What types of molecules (charged, uncharged, chemical structural requirements) can be transported by these different mechanism? • • • • Bulk flow Passive diffusion Facilitated transport Active transport What are the differences between these transport processes? 3 Comparison of Transport Processes Transport Mechanism Passive Diffusion Energy Requirement Saturability and Selectivity None No Bulk Flow None No None Yes Yes Yes Facilitated Diffusion Active Transport 4 Henderson-Hasselbalch Equation Know and be able to use these equations Weak acid pH - pKa = Log Conjugate Base Ionized = Log Acid Unionized Weak base pKa - pH = Log Conjugate Acid Ionized = Log Base Unionized 5 How much of a weak acid (pKa = 3) will diffuse from the stomach to the plasma? Stomach pH 2 1 A 0.1 CB- + H + Log [CB-] -----[A] Log [CB-] -----[A] [CB- ] [A] = = pH - pKa = 2-3 = -1 0.1 1 [A] + [CB-] = 1.1 Plasma pH 7 A 1 CB- + H + 10,000 Log [CB-] -----[A] = pH - pKa Log [CB-] -----[A] = 7-3 = 4 [CB- ] [A] 10,000 = 1 [A] + [CB-] = 10,001 6 How much of a weak base (pKa = 7) will be absorbed from the stomach? Plasma pH 7 Stomach pH 2 1 B + H+ 100,000 CA+ Log [CA+ ] -----[B] Log [CA+] -----[B] [CA+] [B] = pKa - pH =7-2=5 = 100,000 = 100,000 1 [CA+] + [B] = 100,001 B + H+ 1 CA+ 1 Log [CA+] -----[B] = pKa - pH Log [CA+] -----[B] = 7-7 = 0 [CA+] [B] = 1 = 1 1 [CA+] + [B] = 2 7 When is ion trapping most likely to occur in these areas? Body Fluid Range of pH Breast Milk 6.4-7.6 Jejunum, ileum 7.5-8.0 Stomach 1.92-2.6 Prostatic secretions 6.5-7.4 Vaginal secretions 3.4-4.2 Urine 5.0-8.0 Note: You do not need to memorize the pH values for these tissues 8 • Will a weak base (pka 8) be more ionized at pH 6 or pH 8? – pH 6 • Will a weak acid (pka 4) be absorbed better from a stomach where the pH is 2 or where the pH is 3? – pH 2 • What percent of a weak acid (pKa 4 ) will be in the ionized form at pH 3 – [CB]/[A] = 0.1/1 – % in ionized form = 0.1/1.1*100 = 9% 12 What are the advantages and disadvantages of the different routes of drug administration? • See review on page 21 13 From which sites of drug administration do you get first-pass metabolism? First-pass hepatic metabolism? 14 What are the factors which affect the distribution of drugs to the different tissues of the body? • • • • Blood flow Size of the tissue compartment Ability of the drug to permeate the tissue Extent of ionization in the different tissue compartments • Lipid solubility of the drug versus the lipid content of the tissue • Extent of plasma protein binding 15 Which are the vessel rich organs and how does blood flow to an organ affect the distribution of drugs? Vessel-rich organs •Brain •Liver •Heart •Kidney Intermediate group •Muscle •Skin 16 What plasma proteins do drugs bind to? Acidic Drugs • Albumin Basic Drugs • Albumin • Glycoproteins • Lipoproteins 17 What are the characteristics of drugs which cross the placenta and enter the brain? •Drugs which are lipid soluble can cross the blood brain barrier and the placenta by passive diffusion. The more lipid soluble the drug the faster it diffuses into the brain and the faster it crosses the placenta •The more aqueous soluble drugs can only enter the brain or the fetus by active transport or facilitated diffusion. Note: Many drugs are not recognized by the transporters. 18 What are the phase I reactions? • Oxidation • Reduction • Hydrolysis What are the phase II reactions? Conjugation 19 What are the consequences of drug metabolism? •Pro-drug → Drug •Drug → Active and inactive metabolite •Drug → Reactive intermediate •Hydrophobic → Hydrophilic •Exposure of functional groups: -OH, -COOH, -NH2 20 Phase I and Phase II Reactions Phase I Drug Phase II Elimination Conjugation Active metabolite Conjugation Inactive metabolite Conjugation Drug Drug Hydrophobic Hydrophilic What types of drug-drug interactions can occur? 21 22 What is the principle enzymes involved in Phase I reactions and what are some of the other names for this enzyme? • Cytochrome P450 • Microsomal mixed function oxidase • Microsomal drug metabolizing enzyme 23 • Is there more than one cytochrome P450 isozymes? • How is the enzyme be regulated? – Induction – Inhibition – Note: Not all drugs will induce or inhibit the CYP isozymes, only selective isozymes will be inhibited. – NOTE: COMPETION OF ONE DRUG FOR ANOTHER ONLY BECOMES A PROBLEM IF THE DRUGS ARE IN HIGH CONCENTRATIONS. Remember for most drugs you are very low on the place of rate of elimination versus drug concentration – Note: Induction or inhibition of a CYP 450 isozyme will affect the metabolism of all drugs metabolized by that isozyme 24 • What CYP isozyme is induced by cigarette smoke? – CYP1A family • Which CYP isozyme is inhibited by grapefruit juice? – CYP 3A4 in the wall of the intestine 25 • What is the principle location of CYP isozymes? – Liver • What are the substrates, enzymes and cofactors of the CYP450 complex? • Which isozyme is responsible for metabolism of over 50% of the drugs? – CYP 3A4 • What is the significance of the CYP 2D6 enzymes? – Numerous polymorphism have been found 26 Cytochrome P450 Enzyme Complex 27 What are the other types of phase I reactions and what is the primary location of these enzymes? • Oxidative reactions – Flavin monooxygenases (liver) – Amine oxidase (liver and nerve endings) – Dehydrogenase (liver) • Reductive reactions – Liver – Intestinal microflora • Hydrolytic – Esterases: Plasma – Amidases: Liver 28 What are the different types of conjugation reactions that can occur? • • • • • • Glucuronidation Sulfate conjugation N-acetylation Methylation Glutathione conjugation Amino acid conjugation What are the enzymes involved in glucuronidation and hydrolysis of the glucuronide product? 29 Phase II reactions Glucuronidation R-OH + UDP-glucuronic acid UDP-glucuronyltransferase COOH (Liver) O O-R R-O-glucuronide Bile Kidney Intestine Excretion Beta-glucuronidase Intestinal mucosa Intestinal bacteria R-OH + glucuronic acid 30 How Does Age Affect Drug Metabolism? • Age – Less cyc P450 in • Very young • Elderly – Phase II reactions are usually not affected in the elderly – Decreased blood flow to liver in elderly 31 Factors Affecting Drug Metabolism • Pharmacogenetic – Genetic differences in the activities of many metabolic enzymes • Altered activity of CPY enzymes and enzymes involved in conjugation – 2D6 enzymes – N-acetyltransferase: Slow vs fast acetylators 32 What factors determining the amount of drug excreted in the urine? Glomerular Filtration Tubular Reabsorption Tubular Secretion Nephron Excretion = glomerular filtration - tubular reabsorption + tubular secretion - passive reabsorption +passive secretion 33 • How do you speed up the renal elimination of a weak acid? – Make the urine alkaline 34 How are drugs or metabolites excreted from liver to bile? • Passive diffusion • Transporters for – – – – anions bile salts cations neutral organic compounds • How do you enhance biliary excretion? – polar groups – high molecular weight – Conjugation add polar groups and molecular weight 35 What drugs go through the enterohepatic recirculation pathway? Drugs which enter the bile and are: •Lipid soluble enough to be reabsorbed from the wall of the gut •Hydrolyzed in the gut and then reabsorbed •Transported by transporters across the wall of the gut 36 • What is the major route by which drugs are eliminated from the body? – Kidney • What are the minor routes? – bile – skin – lungs – sweat glands – saliva – breast milk 37 What are the basic types of pharmacokinetic drug- interactions? • Involving metabolism – Induction of cyc P450 enzymes – Inhibition of cyc P450 enzymes – Competition of two drugs for the same enzyme – Depletion of endogenous compounds used in conjugation reactions • Displacement from albumin • Competition for transporters • Blood flow to an organ • Changes in pH of a body of fluid 38 Serum Concentration (mg/ml) 5 4 Peak Drug Level 3 2 1 0 0 2 4 6 8 10 12 Time After Drug Administration (hr) 39 Serum Concentration (mg/ml) 5 Duration of Therapeutic Effect 4 3 2 Therapeutic Threshold 1 0 0 2 4 6 8 10 12 Time After Drug Administration (hr) 40 Serum Concentration (mg/ml) 5 4 Toxic Effect 3 Therapeutic Window 2 Therapeutic Effect 1 0 0 2 4 6 8 10 12 Time After Drug Administration (hr) 41 What is the difference between therapeutic window and therapeutic index? • Therapeutic window is the plasma concentration range where therapeutic effect occurs without toxic effects • Therapeutic index is: TD50/ED50 42 How do you determine bioavailability? F= AUC for route being studied AUC after IV administration What factors will alter bioavailability? 43 What is the Volume of Distribution of a drug? Xo mg Vd (L) = Cp (mg/ml) 44 Plasma Drug Concentration (μg/ml) How do you measure the concentration of drug in the plasma at time T = 0? 10 Cp 8 6 4 2 0 10 20 30 40 50 60 Time (Hours) 45 What does it mean if a drug has the following Vd in a 70 kg person? • • • • 500 L 10 L 35 L 42 L 46 • What is meant by t1/2? • How many half-lives does it take for the drug concentration to reach steady-state? – 4 to 5 half-lives • How many half-lives does it take for the drug to be eliminated from the body? – 4 to 5 half-lives • What is kel? – Rate constant for elimination • What are the units for kel? – 1/time • How does kel change with plasma concentration? – It remains constant at low concentrations of drug 48 Plasma Drug Concentration (μg/ml) Is this drug being eliminated by first order or zero order kinetics? 100 80 60 Zero order 40 20 2 4 Time (Hrs) 6 8 What is the half-life of this drug? Half-life changes with plasma concentration If you double the dose how long does it take to eliminate the drug from the body? Twice as long What happens to steady state plasma levels if you double the dose? Greater than 2x plasma level 49 Plasma Concentration (mg/L) Effects of Doubling Dose Zero Order Kinetics 25 20 15 10 8 16 24 32 40 48 56 64 72 80 88 96 Time (hrs) NOTE: Drug is entering the body faster than it leaves51the body Plasma Drug Concentration (μg/ml) Is this drug being eliminated by first order or zero order kinetics? 10 8 6 1st order 4 2 0 10 20 30 40 50 60 Time (Hours) What is the half-life of this drug? 10 hours If you double the dose how long does it take to eliminate the drug from the body? 4 to 5 half-lives or 40-50 hours --- time is independent of plasma levels What happens to steady state plasma levels if 52 you double the dose? Plasma levels double Plasma Concentration (mg/L) Effects of Doubling Dose 1st Order Kinetics 8 6 4 2 8 16 24 32 40 48 56 64 72 80 88 96 Time (hrs) Note: Drug enters body at the same rate it is leaving the 53 body Is this drug being eliminated by first order or zero order kinetics? 1st order What is the half-life of this drug? 10 hours How long will it take to reach steady state plasma concentration if this drug is given by continual IV infusion? 40 to 50 hours 54 1st Order Zero Order Elimination Exponential Linear Half-life Constant with Changes with changing plasma plasma concentrations concentration Eliminated per unit time Constant Fraction Constant Amount Clearance Rate of elimination/Cp Time required to eliminate drug Double the dose 4-5 Half-lives Maximum rate of elimination process Based on amount of drug given Double plasma concentration Greater than twice plasma concentration 57 What is meant by the clearance of a drug from the body, how is it calculated and what are the units? • Theoretical volume of fluid from which a drug is completely removed in a given period of time. • For a drug eliminated by first order kinetics Rate of elimination (mg/min) Clearance (CL)(ml/min) = Concentration (mg/ml) 58 How is clearance related to Vd and t1/2? CLT = 0.7 X Vd t1/2 If CL changes but not Vd what happens to the t1/2 ? Half-life is inversely proportional to clearance. If volume of distribution does not change and clearance decreases then the half-life will increase. 59 How does rate of elimination change with drug concentration for a drug eliminated by zero order kinetics? • V = Vmax • Rate of elimination of the drug from the body is based on the maximum rate of the rate limiting step in the elimination process (metabolizing enzyme, transporter ect.) 60 What is meant by saturation kinetics? • Low doses first order kinetics occur • As dose increases the half-life increases and elimination is by Michaelis-Menton kinetics • At high doses rate of elimination is dependent on the maximum rate of the elimination pathway What is meant by flow dependent elimination? • Rate of clearance is dependent on the rate of blood flow through the organ 62 Plasma Concentration µg/ml Are drugs A or B being eliminated by first or zero order kinetics? 10.0 A 1st order 1.0 B Zero order 0.1 0 25 50 75 100 125 150 Time (min) Why isn’t the curve for Drug B linear? Two compartment distribution 63 Plasma Concentration µg/ml Two Compartment Model 10.0 1st Order One compartment a 1.0 b Two Compartment 0.1 0 25 50 75 100 125 150 Time (min) What is determines the two phases of the curve for Drug B? Alpha-slope is due to redistribution of the drug from the vessel rich compartment to other compartments. Betaphase is due to metabolism and/or excretion 64 Two Compartment Model for Drugs Acting on the CNS • Note: The more lipid soluble the drug the faster the rate of on set of action – More lipid soluble the faster the drug crosses the blood brain barrier • Note: `The more lipid soluble the drug the shorter the duration of action – The faster the redistribution phenomenon 65 How do you calculate the maintenance dose for IV administration? Dosing rate (mg/min/kg) = CL X Css How do you calculate loading dose? LD = Vd x Css How do you calculate the oral dose? Dose = (CLp (ml/min) x Cpavg (mg/ml)) x Dosing interval (Hr) F 66 How do decreases in body weight affect the following parameters? • • • • • • t1/2 No change Vd Decrease CL Decrease Loading dose Decrease Oral dose Decrease IV maintenance dose Decrease 67 Given the following properties of a drug for a 70 kg man: Bioavailability = 0.8 CL = 3.5 L/hr Half-life = 8 hours Effective plasma concentration = 1 mg/ml What is the Vd for a 70 kg male? 0.7 x Vd CL = t1/2 CL x t1/2 Vd = 0.7 3.5 L/hr x 8 hr Vd = 0.7 Vd = 40 L 68 Given the following properties of a drug for a 70 kg man: Bioavailability = 0.8 CL = 3.5 L/hr Half-life = 8 hours Vd = 40 L Effective plasma concentration = 1 mg/ml What is the t1/2 for an individual whose CL is ½ the normal rate? 0.7 x Vd CL = NOTE: If CL is decreased by t1/2 50%, t1/2 will increase by 50% t1/2 = 0.7 x Vd CL 0.7 x 40 L t1/2 = 1.75 L/hr t1/2 = 16 hours 69 Given the following properties of a drug for a 70 kg man: Bioavailability = 0.8 Vd = 40 L CL = 3.5 L/hr Half-life = 8 hours Effective plasma concentration= 1 mg/ml What is the loading dose for a 70 kg male? LD = Vd X Css LD = 40 L x 1 mg/ml x 1000 ml/L x 1 mg/1000 mg LD = 40 mg LD = 40 L x 1 mg/L = 40 mg LD = 40 mg/70 kg = 0.57 mg/kg 70 Given the following properties of a drug for a 70 Kg man: Bioavailability = 0.8 Vd = 40 L Cl = 3.5 L/hr Half-life = 8 hours Effective plasma concentration= 1 mg/ml What is the dose required for IV maintenance in a 100 kg male? Dose = CL/70 kg x Css x Body Weight Dose = 3.5 L/hr x 1 mg/L x (100 kg/70 kg) Dose = 5 mg/hr 71 Given the following properties of a drug for a 70 kg man: Bioavailability = 0.8 Vd = 40 L Cl = 3.5 L/hr Half-life = 8 hours Effective plasma concentration= 1 mg/ml What would the oral dose be for a 100 kg if you wanted to give the drug every 8 hours? Dose = CL x Cavg x Dosing interval x body weight F x 70 kg Dose = 3.5 L/hr x 1 mg/L x 8 hr x 100 kg 0.8 x 70 kg Dose = 50 mg every 8 hours 72 Plasma Concentration (mg/L) Fluctuations in Plasma Concentration with Dosing Intervals 25 20 15 10 5 8 16 24 32 40 48 56 64 72 80 88 96 Time (hrs) 73