2. CLEARANCE (CL) describes the efficiency of irreversible elimination of a drug from the body by excretion of unchanged drug. Metabolic conversion of the drug. Clearance is defined as “the volume of blood cleared of drug per unit time” Clearance are additive total clearance = (CL ) + (CL ) HR CLINICAL PHARMACOKINETICS

3. Clearance determines the maintenance dose rate (MD) required to achieve a desired serum drug concentration (SDC) at steady state. MD (mg/hr) = desired SDC (mg/L) x CL (L/hr) or = C ss X CL Why is CL important ?

4. VOLUME OF DISTRIBUTION (V d ) It is the parameter relating the SDC to the total amount of the drug in the body. Vd (L) = Amt of drug in the body (mg)/SDC (mg/L) or = Dose/SDC 0 How is V d measured ?

5. V d is used for calculating the loading dose (LD). LD (mg) = V d (L) X desired SDC (mg/L) Why is V d important ? V d predicts the efficiency of hemodialysis to remove the drug from the body.

6. HALF-LIFE (T 1/2 ) T 1/2 is the time taken for the amount of drug in the body (or the SDC) to fall by half. T 1/2 (hr) = 0.693 X V d /CL

7. Why is half-life important ? Half-life is a major determinant of : The duration of action after a single dose. The time required to reach steady state. The dosing frequency.

8. BIOAVAILABILITY AND FIRST PASS CLEARANCE C.Intestinal motility Dissolution of slowly soluble drugs (digoxin, sustained release formulations) Chemical degradation or metabolism by microflora Affected by : drugs (opiates, anticholinergics, metoclopramide); disease states (gastroenteritis) D.Drug interactions in the gut lumen Complexation (tetracyclines with divalent metal ions) Adsorption (anion exchange resins) Food interactions (many antibiotics) E.Passage through the gut wall Physico-chemical characteristics of the drug (quaternary ammonium compounds) Metabolism by enzymes in the intestinal endothelium Absorption is the extent to which intact drug is absorbed from the gut lumen into portal circulation. A.Dissolution Physico-chemical properties of drug Crystal size and form Excipients Special dosage forms (sustained release, enteric coated) pH (stomach and small intestine) B.Gastric emptying rate Stability of drug at acid pH Solution or solid dosage forms (liquids and small particles empty more quickly) Affected by: food; antacids; drugs (opiates, anticholinergics, metoclopramide); disease (autonomic neuropathy) Table 1 Determinants of drug absorption from the gut

9. First pass clearance is the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation.

10. Hepatic enzyme % extracted Bioavailability Activity first pass (% escaping first pass extraction) A.Low extraction ratio drug Normal 2 98 Doubled (induced) 4 96 Halved (inhibited) 1 99 B.High extraction ratio drug Normal 90 10 Doubled (induced) 95 5 Halved (inhibited) 83 17 All the dose is assumed to be absorbed intact from the gut lumen. The low extraction ratio example is characteristic of theophylline which has an intrinsic clearance (see previous article Aust Prescr 1990; 13:88 – 9) of about 15 mL/min. The high extraction ratio example is characteristic of verapamil which has an intrinsic clearance of about 15 000 mL/min. Liver blood flow is normally around 1500 mL/min. Table 2 Effects of increase or decrease in hepatic drug metabolising enzyme activity on bioavailability Why is first pass clearance important ? Why is first pass clearance important ? Variability in drug response. Relationship between oral and intravenous or parenteral doses. Alternative route of administration. Drug interactions. Liver disease.

11. Bioavailability is the fraction of the dose which reaches the systemic circulation as intact drug. It depends both on how well the drug is absorbed and how much escapes being removed by the liver before reaching the systemic circulation.

12. Absolute Bioavailability (F) is a measure of bioavailability of a drug given by any routes against an intravenous route. F = AUC 0 /AUC i If different doses are used, then F = AUC 0 x Dose i /AUC i X Dose 0

13. Relative Bioavailability (f) is a measure of bioavailability of one formulation against a second (reference) formulation given by the same route. f = AUC A /AUC B

14. Bioequivalence is a clinical definition referring to two formulations of a drug with similar extents and rates of absorption that there is likely to be no clinically important difference.

15. Therapeutic Equivalence. If two formulations are bioequivalence, they are usually as having therapeutic equivalence provided that no impurity or pyrogen have the same amounts of stereoisomeric active ingredients.

16. Why is bioavailability important ? Bioavailability is the major parameter that indicates how much drug reach systemic circulation. Bioavailability study is needed for drugs which have one or more of the following characteristics : 1. Narrow therapeutic index : digoxin, theophylline, antiepileptic drugs, antibiotics, 2. Lack of therapeutic effects is dangerous : digoxin, antiepileptic drugs, antibiotics, 3. Poor absorption : digoxin, phenytoin, carbamazepine 4. Non-linear elimination kinetics : phenytoin 5. High first pass clearance : verapamil

17. FDA approves the drug formulations that have bioavailability in the range of 80-125% of the original or innovator’s brand, this may not be appropriate in certain situations, e.g., Case A. Changing from a formulation with bioavailability of 80% to a formulation with 125% bioavailability. Since F x MD= Css x CL Css=F x MD/CL If a formulation with 80% availability is used Css1=0.8 x MD/CL If switching to a formulation with 125% availability Css2=1.25 x MD/CL Css2/Css1=1.25/0.8 = 1.56 The SDC increases about 50% from initial levels

18. Case B. Changing from a formulation with bioavailability of 125% to a formulation with 80% bioavailability. Css2/Css1 = 0.8/1.25 = 0.64 The SDC decreases about 35% from initial levels Consider the case of aminoglycosides, if patients switch to formulations with very high bioavailability they may suffer toxic effects at high peak and high trough levels.

19. Predicting how drugs will behave pharmacokinetically. Known parameters Total clearance (L/hr) 80 3 7 Volume of distribution (L) 500 25 420 Fraction excreted unchanged 0.1 0.1 0.8 Liver blood flow (L/hr) 90 90 90 Predicted Renal clearance (L/hr) (fraction 8 excreted unchanged X total Cl) Hepatic clerance (L/hr) 72 Hepatic extraction ratio (hepatic Cl/liver blood flow) 0.8 Maximum oral bioavailability (%) 20 Affected by induction/inhibition of liver enzymes when given orally Yes Drug A Drug B Drug C Affected by liver blood flow when given intravenously Yes Decrease dose in liver disease Yes Decrease dose in renal failure No Half-life (hr) = 0.693 X Vd/Cl 4 Likely dosing schedule (times/day) 6 Time to reach steady state (hr) 20

20. Q uestions C omments Q uestions C omments &