1. 1 Single-dose kinetics Plasma [Drug] curve Upon administration [drug] plasma reaches a max Then begins to decline as the Drug is eliminated Cp max = max plasma [drug] t max = time to reach Cp max AUC= area under the curve= These measures are useful for comparing the bioavailability of different pharmaceutical formulation 59-291 Section 1, Lecture 6

2. 2 Bioavailability- the fraction of the administered dose that reaches the systemic circulation= AUC oral /AUC IV AUC oral can be affected by: -rate of tablet disintegration -drug solubility -sequestration by food -gastric acid and gut enzyme inactivation

3. 3 Continuous and multiple dose kinetics Steady-State Principle: Steady-State Principle: for drugs exhibiting first-order pharmacokinetics [Drug] [Drug] plasma [Drug] urine, rate= [Drug] x k abs rate= [Drug] plasma x k e Rate of administration or absorption Rate of elimination Initially rate of admin. or absorption greater than rate of elimination because initially [Drug] plasma is low -rate of elimination gradually increases as [Drug] plasma increases and reaches a plateau. This is termed the steady-state concentration.

4. 4 Since the time to reach steady-state is composed of 2 first-order processes, it also obeys the rules of 1 st order reactions. It takes 5 half-lives to complete a 1 st order process: (1/2 n )= 1/ 2x2x2x2x2= 1/32= 0.03 or 3% remains or 97% produced after 5 half-lives Time required to reach the steady state is independent of the drug dose and frequency of drug administration

5. 5 Half-Life The time it takes for one half of the original amount of a drug in the body to be removed A measure of the rate at which drugs are removed from the body Dug concentration100502512.56.253.125 Hours after peak concentration 0816243240 Number of half- lives 012345 Percentage of drug removed 05075889497

6. 6 Steady-State concentration depends on: -drug dose/unit time; and t ½ of the drug -if you double either, you get the same effect

7. 7 -an intermittently administered drug will accumulate to a steady- state at the same rate as a drug given by continuous infusion BUT the fluctuations in [drug] plasma will be less with the latter method

8. 8 Dosage Calculations; Loading dose- dose to establish a rapid therapeutic [drug] plasma = V d x desired [drug] plasma dose/Cp0 In the case of toxic drugs (digitalis) Loading dose is divided into several portions and given over a long time Maintenance dose= dose required to maintain a desired steady-state Rate of elimination (in hours) x dosage interval in hours At steady state: rate of elimination=rate of administration (absorption) rate of elimination = Cl x avg [Drug] steady-state plasma

9. 9 Example for Gentamicin: [Gentamicin] steady-state plasma = 2 mg/L Cl gentamicin =100 mL/min rate of elimination = Cl x avg [Drug] steady-state plasma = 0.1 L/min x 2 mg/L = 0.2 mg/min What is the maintenance dose for administration once every 8 h? Maintenance dose = Rate of elimination (in hours) x dosage interval in hours = 0.2 mg/min x 60 min/h x 8h = 96 mg

10. 10 Practice questions Define bioavailability and list the parameters that are useful for comparing different formulations –the fraction of the administered dose that reaches the systemic circulation= AUCoral/AUCIV –CP max –T max –AUC oral

11. 11 List the parameters that affect bioavailability of orally administered drugs –rate of tablet disintegration –drug solubility –sequestration by food –gastric acid and gut enzyme inactivation