Pharmacokinetics

Dr/Mustafa Shahin

Drug Pharmacokinetics Following Single IV Administration

Introduction: During IV administration, the drug is directly introduced into the systemic circulation. The Drug is distributed to all parts of the body and then eliminated through one or more of the elimination pathways. Drud distribution and elimination occur simultaneously at different rates depending on the pharmacokinetics parameters of the drug. The volume of distribution (Vd) of the drug describes the extent of drug distribution to different tissues, which is dependent on the affinity of the drug to these tissues. The drug total body clearance (CLT) describes the efficiency of different eliminating organs, such as the liver and the kidney. The drug half-life (t1/2) and the elimination rate constant (K) determine the rate of decline of the drug profile in the body. Elimination Rate Constant (K): Determined by measuring the decrease in amount at different time intervals. Rate constant: The velocity at which elimination process occurs. Dependent on the order of elimination. Most of drugs are eliminated by 1st order kinetics. Zero order elimination: The Rate of elimination is constant and is equal to the zero order eliminatin rate constant (K0). K0 has units of mass/time. Drug decreases with constant rate: dA/dt = - K0 A = A0 K0 t A: Amount of drug at any time. A0: Amount of drug at time zero i.e. initial amount. 1

Pharmacokinetics

Dr/Mustafa Shahin

Plotting the amount of drug (A) versus time (t) on a Cartesian graph paper will give a straight line.

First order elimination: dA/dt = -K A The Rate of drug elimination is dependent on K and A. Rate of elimination decreases with time due to drug decrease in the body. K has units of time-1. Plotting the amount of drug (A) versus time (t) on a Cartesian graph paper will give a curve.

Pharmacokinetics

Dr/Mustafa Shahin

Plotting Ln A versus time (t) on a Cartesian graph paper will give a straight line.

Plotting Log A versus time (t) on a Cartesian graph paper will give a straight line.

Pharmacokinetics

Dr/Mustafa Shahin

Plotting A versus time (t) on a semi-log graph paper will give a straight line.

Clinical Importance of the elimination rate constant: K rate of elimination Drugs which are eliminated rapidly have short duration effect. During multiple drug administration, drugs eliminated rapidly need to be given more frequently to maintain effective drug level in the body while slowly eliminated drugs should be given less frequently. In case of organ dysfunction, rate of elimination will be decreased, so smaller doses are required or doses should be given less frequently.

Pharmacokinetics

Dr/Mustafa Shahin

Volume of Distribution (Vd): After IV administration, the drug is distributed via the systemic circulation to all parts of the body, leaving only a fraction of the administered dose in the sampling compartment (the blood). Drugs are not distributed equally to all tissues because different drugs have different affinities to different tissues. This means that the amount of the drug and the concentration of the drug in the sampling compartment will be different for different drugs depending on the administered dose and the drug distribution characteristics. Relationship between drug amount in the body and drug blood concentration:

Vd is the parameter that relates the amount of drug in the body to the drug concentration in the blood. Vd does not represent a real volume. Vd is an independent PK parameter; that does not depend on other parameters. Drug blood concentration-time profile follows 1st order and can be described as follows:

Determination of Vd:

Pharmacokinetics

Dr/Mustafa Shahin

It depends on patient weight. Vd has units of volume (Liter) or volume/ weigt (Liter/Kg). Clinical importance of Vd: Vd allows calculation of the dose required to achieve a certain blood concentration of the drug. Vd also allows calculation of the expected drug blood concentration achieved after administration of a certain dose. Drugs that are extensively distributed to the tissues will have a larger Vd and will require larger doses to achieve a certain drug blood concentration.

Pharmacokinetics

Dr/Mustafa Shahin

Half Life (t): The time required for the drug amount in the body or the drug blood concentration to decrease by one half (50%). Zero order elimination:

t depends on the drug amount (and the concentration) and K0.

First order elimination:

t is constant.

Pharmacokinetics
Clinical importance of t It reflects the rate of drug elimination.

Dr/Mustafa Shahin

Drugs with short t (K) eliminated faster. N.B: t and k depend on CLT and Vd. Different patients have different t for the same drug. t Indicates how fast the drug is eliminated from the body. t Has units of time. Total Body Clearance (CLT): The volume of plasma or blood that is completely cleared from the drug per unit time. It measures the efficiency of all eliminating organs in metabolising/excreting the drug. It has units of Vol/Time (or Vol/Time/Weight) CLT of drug is constant and independent of concentration. Organ clearance: the clearance of the drug by a specific organ. CLT is the sum of clearances of all eliminating organs. CLT = Renal CLT + Hepatic CLT + Lung CLT Relation-ship between CLT, Vd and K: CLT and Vd (the two independent PK parameters) are the two parameters that determine K and t (the dependent PK parameters). CLT = K Vd

Pharmacokinetics

Dr/Mustafa Shahin

Total Body Clearance and Volume of distribution are Independent PK parameters:

Organ dysfunction affects CLT without affecting Vd. Changes in distribution will affect Vd without affecting CLT. CLT does not mean faster elimination rate, as Vd should be considered. If two different drugs have the same CLT; the drug with higher Vd, has longer t lower K. If two different drugs have the same Vd; the drug with lower CLT will have longer t and lower K. Clinical Importance of CLT: For the same drug (same Vd), CLT means rate of elimination. CLT is used as a parameter for organ eliminating function. The clearance of Creatinine is used as a measure of kidney function. Area under the Curve (AUC): AUC is the Integral of the blood concentration with respect to time from zero time to time infinity. It has a unit of mass.time/vol. Factors affecting AUC:

AUC is directly proportional with dose and inversely proportional with CLT Calculation of AUC can be determined through trapezoidal rule. 9

Pharmacokinetics
Clinical importance of AUC:

Dr/Mustafa Shahin

AUC is used to compare dug amount that reaches systemic circulation after different routes of administration i.e. determination of bioavailability. AUC can be used to compare the clearance of a drug in different individuals after administration of the same dose.

Factors affecting the drug blood concentration-time profile after a single IV bolus dose:
1. Dose: dose Cp0 & AUC however the dose does not affect k, Vd or CLT. 2. Volume of Distribution: Administration of the same dose of the same drug to a group of different individuals who have different Vd results in Cp0 in the individuals with Vd. 3. Total Body Clearance: Administration of the same dose of the same drug to a group of different individuals who have different CLT results in different rates of decline if the Vd is similar in these individuals. CLT ( K & t1/2) and AUC.

Dr/Mustafa Shahin 0100 751 35 38

10