上海交通大学：《药理学 Pharmacology》课程教学资源（讲义课件）Chapter 2：Pharmacokinetics（2）

Chapter 2: Pharmacokinetics (2) Prof.R.D.Ye 2012-09-12

Chapter 2: Pharmacokinetics (2) Prof. R.D. Ye 2012-09-12

Quantitative Pharmacokinetics To derive and use expressions for pharmacokinetic parameters,the first step is to establish a mathematical model that accurately relates the plasma drug concentration to the rates of drug absorption,distribution,and elimination.The one- compartment model is the simplest model of drug disposition,but the two-compartment model provides a more accurate representation of the pharmacokinetic behavior of many drugs

Quantitative Pharmacokinetics To derive and use expressions for pharmacokinetic parameters, the first step is to establish a mathematical model that accurately relates the plasma drug concentration to the rates of drug absorption, distribution, and elimination. The one￾compartment model is the simplest model of drug disposition, but the two-compartment model provides a more accurate representation of the pharmacokinetic behavior of many drugs

One-compartment model One-compartment model Ka Ke Absorption Drug- Elimination D A One-compartment model: V1=X1/Co V1:Apparent volume of distribution X1:Amount of drug in the compartment Co:Drug concentration at initial time

One-compartment model: V1 = X1 / C0 V1: Apparent volume of distribution X1: Amount of drug in the compartment C0: Drug concentration at initial time One-compartment model

Two-compartment model Two-compartment model Blood Ka Ke Absorption Drug Elimination Kd Drug Tissues B Two-compartment model: Central compartment:Heart,lung,liver,kidney Peripheral compartment:Skin,muscle,fat tissue,etc. (1)Drug enters into the central compartment,(2)then distribute to peripheral compartment;(3)eventually,drug is eliminated from the central compartment

Two-compartment model Two-compartment model: Central compartment: Heart, lung, liver, kidney Peripheral compartment: Skin, muscle, fat tissue, etc. (1) Drug enters into the central compartment, (2) then distribute to peripheral compartment; (3) eventually, drug is eliminated from the central compartment

Drug distribution Apparent volume of distribution Plasma (4L) ● Interstitial fluid (10L) Intracellular fluid (28L) B Calculation of the Va 50.00 (/6w) Distribution phase (a) 5.00 0.50 C Elimination phase(B) 0.05 0.00 0 Time 500mg injected IV Va Dose 500 mg Co 5 mg/L =100L C

(Apparent)volume of distribution The calculated volume of distribution (Vd)of a drug is an apparent volume that can be defined as the volume of fluid in which a drug would need to be dissolved to have the same concentration in that volume as it does in the plasma (B).The graph(C)provides an example of how the Vd is calculated.In this example,a dose of 500 mg was injected intravenously at time zero,and plasma drug concentrations were measured over time.The terminal elimination curve B was extrapolated back to time zero to determine that the plasma drug concentration at time zero,CO,was 5 mg/L.Then the Vd was calculated by dividing the dose by the Co.In this case,the result was 100 L

• The calculated volume of distribution (Vd) of a drug is an apparent volume that can be defined as the volume of fluid in which a drug would need to be dissolved to have the same concentration in that volume as it does in the plasma (B). The graph (C) provides an example of how the Vd is calculated. In this example, a dose of 500 mg was injected intravenously at time zero, and plasma drug concentrations were measured over time. The terminal elimination curve (β) was extrapolated back to time zero to determine that the plasma drug concentration at time zero, C0, was 5 mg/L. Then the Vd was calculated by dividing the dose by the C0. In this case, the result was 100 L. (Apparent) volume of distribution

(Apparent)volume of distribution Although the Vd does not correspond to an actual body fluid compartment,it does provide a measure of the extent of distribution of a drug.A low Vd that approximates plasma volume or extracellular fluid volume usually indicates that the drug's distribution is restricted to a particular compartment (the plasma or extracellular fluid).The anticoagulant warfarin has a Vd of about 8 L,which reflects a high degree of plasma protein binding.When the Vd of a drug is equivalent to total body water(about 40 L,as occurs with ethanol),this usually indicates that the drug has reached the intracellular fluid as well

• Although the Vd does not correspond to an actual body fluid compartment, it does provide a measure of the extent of distribution of a drug. A low Vd that approximates plasma volume or extracellular fluid volume usually indicates that the drug's distribution is restricted to a particular compartment (the plasma or extracellular fluid). The anticoagulant warfarin has a Vd of about 8 L, which reflects a high degree of plasma protein binding. When the Vd of a drug is equivalent to total body water (about 40 L, as occurs with ethanol), this usually indicates that the drug has reached the intracellular fluid as well. (Apparent) volume of distribution

Distribution:fluid compartments TOTAL BODY WATER 60%Body weight 40 -45 Liters EXTRACELLULAR FLUID INTRACELLULAR FLUID 20%Body weight 40%Body weight 10 -20 Liters 25 35 Liters INTRAVASCULAR FLUID INTERSTITIAL FLUID (Plasma) 16%Body weight 4%Body weight 10-12 Liters 2-3 Liters

Distribution: fluid compartments

Drug distribution Apparent volume of distribution Plasma (4L) Interstitial fluid (10L) Intracellular fluid (28L) A B Calculation of the Vd 50.00 Distribution phase (a) 5.00 0.50 Co Elimination phase (B) 6nup 0.05 0.00 0 Time 500mg Dose 500mg injected IV Vd= =100L Co 5 mg/L C

(Apparent)volume of distribution Some drugs have a Vd that is much larger than total body water.A large Vd may indicate that the drug is concentrated intracellularly,with a resulting low concentration in the plasma.Many weak bases, such as the antidepressant fluoxetine(Prozac),have a large Vd(40-55 L)because of the phenomenon of intracellular ion trapping.Weak bases are less ionized within plasma than they are within cells because intracellular fluid usually has a lower pH than extracellular fluid.After a weak base diffuses into a cell,a larger fraction is ionized in the more acidic intracellular fluid.This restricts its diffusion out of a cell and results in a large Vd

• Some drugs have a Vd that is much larger than total body water. A large Vd may indicate that the drug is concentrated intracellularly, with a resulting low concentration in the plasma. Many weak bases, such as the antidepressant fluoxetine (Prozac), have a large Vd (40‐55 L) because of the phenomenon of intracellular ion trapping. Weak bases are less ionized within plasma than they are within cells because intracellular fluid usually has a lower pH than extracellular fluid. After a weak base diffuses into a cell, a larger fraction is ionized in the more acidic intracellular fluid. This restricts its diffusion out of a cell and results in a large Vd. (Apparent) volume of distribution