PHARMACOKINETICSDr. Henny Lucida, Apt

Topics Introduction to pharmacokineticsPharmacokinetic modelsOne-compartment open modelMulticompartmental modelsPharmacokinetic model of oral absorptionDrug Distribution and protein bindingStudent presentation & Discussion

Introduction Various routes of administration

IntramuscularSubcutaneousIntravenousIntrasynovialIntracardiacIntrathecalEyeNasalEarOralSublingualBuccalRectalVaginalUrethralTopical

Dose of drug administeredDrug conc. in systemic circulationABSORPTIONDrug conc at site of actionPharmacologic effectClinical responseToxicityEfficacyDrug in tissuesOf distributionDrug metabolizedOr excretedDISTRIBUTIONELIMINATIONBiopharmaceuticsPharmacokineticsPharmacodynamics

Drug conc-response relationshipMTCMEC

ADME ProcessesAbsorptionDistributionMetabolismExcretion

Drug Disposition

Pharmacokinetic model

Compartment models :

Mammillary modelCatenary modelPhysiologic model

Mammillary model

One open compartment modelAssumptionsThe drug in the blood is in rapid equilibrium with drug in the extravascular tissuesThe drug is mixed instantaneously in blood or plasmaDrug elimination follows first order kinetics

Multicompartment modelAssumptionsThe drug would be transferred to other compartments (k12, k21, k13, k31)The transferred lasted when equilibrium is reached, at this point the change in drug conc in central comp will be equal to that in other compsEquation for Cp vs t curve is a summation of several equation of first order kinetics

Two compartment open model

Diagram of a two compartment model

ParametersOne open compartment modelk0 or ka, kel, t1/2, C, X, Vd appMulti compartment model k0 or ka, kel, t1/2, C, X, Vd app, and k12, k21, k13, k31

EquationsThe change of the amount of drug in the body according to 1st order kin:

Vd appX = Vd x CVd = a proportionality constant that relate X and CC

Vd apparentHas no physiologic meaningFor some drugs, Vd app exceed the total body water (60 L)

Vd app of some drugs

Vd app of digoxin is much larger than body volume drug must be extensively distributed into tissue, leaving low conc in the plasma, thus the body as a whole appears to have a large volume, of distribution

Kel and t1/2 elKel is calculated from the slope of the first order plot of Cp vs tAs for first order kinetics:

Values for kel and t1/2 el of some drugs

One compartment model, intravenous injection

Plot of Cp vs t for a bolus iv dose

Plot of ln C vs t

Equation to calculate kelSince X0 = the amount of drug injected intravenously = the intravenous doseThen, for an iv bolus:

Example calculations:After an iv dose of 500 mg, V=30 L, kel = 0.2/hr. Calculate Cp at 2 & 4 hr.Using eq. Andthen

C0p = 500/30 = 16.7 mg/LCp2hr = 11.2 mg/LCp4hr = 7.5 mg/L

Calculation of kel using urinary excretion dataKel = ke + knr

ClearanceRenal ClearanceSystemic ClearanceVd app

AUC

AUC calculated by trapezoidal rule

Intravenous infusionModel:

Profile of Cp vs t for slow iv infusion

A semilog plot of Cp vs t for iv infusion

Cp vs t profile for fast iv infusion

Cp vs t profile for iv infusion with a loading dose

Steady state concentration

Plasma drug concDuring continuous constant rate iv infusion, drug conc in plasma increase according the above eq but eventually approach a constant value or plateau called infusion equilibrium, which actually is a steady-state situation

Correlation of C and CssA semilog plot of (Css-C)/Css vs time yields a straight line with a slope of kel/2.303, then kel can be calculated.

Application of equationsFor theophylline with a t1/2= 4 hours, the time to reach Css = 16 hr (94%)We could calculate how long it might take to reach a therapeutic conc (10 mg/L).Since: k0=60mg/hr, kel=0.17/hr, Vd=25L, and

then,0.708 = 1-e-0.17*t, thus 0.292 = e-0.17*ttherefore -0.17*t = -1.231 or t = 7.24 hr

C at post infusionKel can also be calculated from data collecting after stopping the infusion

or

Cmax = the drug conc in plasma when the infusion was terminatedt = the time after stopping the infusionT = the infusion duration time

Calculation of Vd by using Css and AUC data

Infusion with a loading doseDrugs with t1/2 >>>> (long half life)

the time to reach steady state will be very long

it is desirable to administer an iv loading dose just before starting the infusion. The loading dose should be large enough to yield the desired Css immediately. The infusion rate should be fast enough to maintain this conc

Loading doseX0 = Css * VdThe amount of drug in the body after simultaneous an iv loading dose and initiation of constant rate iv infusion:

The amount of drug in the body is constant throughout the time course of drug adm