Pharmacokinetics 2 General Pharmacology M212 Dr. Laila M. Matalqah Ph.D. Pharmacology

Drug clearance Drugs clearance by: Hepatic metabolism Excretion (elimination) into the urine or into the bile These elimination process cause plasma conc of drugs to decrease exponentially .

1. Metabolism Metabolism: is the process of transforming lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, and other tissues, such as the kidney and the intestines Some agents are initially administered as inactive compounds (prodrugs) and must be metabolized to their active forms.

Clearance Clearance : is the amount of drug eliminated from the body per unit time CL: clearance Vd: Volume of distribution t1/2: half life of drug (the time it takes to reduce the drug plasma conc by half) T1/2

Kinetics of metabolism First-order kinetics (Linear kinetics) A constant fraction of drug is metabolized per unit of time. The rate of drug metabolism is directly proportional to drug plasma concentration and drug dose. The metabolism of drugs obey Michaelis-Menten kinetics:

Kinetics of metabolism Zero-order kinetics (nonlinear kinetics). A constant amount of drug is metabolized per unit of time. The rate of drug metabolism is independent of drug plasma concentration and drug dose. The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time

Kinetics of metabolism Zero-order kinetics: (nonlinear kinetics). E.g., a few drugs, such as aspirin, ethanol, and phenytoin

Reactions of drug metabolism Phase I reactions: to convert lipophilic molecules into more polar molecules Phase I without P450 system: oxidation, reduction or hydrolysis reactions. Example ethanol oxidation Phase I metabolism using cytochrome P450 system Cytochrome P450 (CYP450), is composed of many families of isozymes that are located in the liver and GI tract

Reactions of drug metabolism Phase I reactions: Six isozymes are responsible for the majority of P450- catalyzed reactions: CYP3A4/5 CYP2D6 CYP2C8/9 CYP2C19 CYP2E1 CYP1A2.

A. Enzyme Induction Substrate: Drug is metabolized by the enzyme system Inducer: Drug that will increase the synthesis of CYP450 enzymes It may induce the activity of these enzymes by inducing the expression of the genes encoding the enzyme or by stabilizing the enzymes

How to solve this problem: A. Enzyme Induction The Overall effect is : increased biotransformation of the substrate drugs significant decreases in plasma drug concentrations Decrease in effect of the substrate drug (Target) if the metabolite is inactive Decreased therapeutic drug effect. How to solve this problem: To get the same effect from the target drug, you may need to INCREASE the dose of the target drug

Drug metabolism Effect Target Drug Cytochrome P450 enzymes Metabolite

Enzyme inducers reduce the effect of the target drug Less Effect Enzyme Inducing Drug Cytochrome P450 enzymes +++ Metabolite +++

Enzyme Inducers: Examples Rifampicin Phenobarbitone Carbamazepine Phenytoin Cigarette smoking

B. Enzyme Inhibition Inhibitor: Drug that will decrease the metabolism of a substrate Inhibition of CYP isoenzyme activity through competition for the same isoenzyme. This drug interactions can lead to serious adverse events Example: omeprazole is a potent inhibitor of CYP isozymes responsible for warfarin metabolism. what is the result of this drug–drug interaction? If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions

Enzyme inhibitors increase the effect of the target drug Greater Effect Enzyme Inhibiting Drug Cytochrome P450 enzymes - - - Metabolite - - -

Enzyme Inhibition Overall effect is an increase in effect of the target drug To get the same effect from the target drug, you may need to DECREASE the dose. For example, omeprazole is a potent inhibitor CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.

Enzyme Inhibitors Substrate Inhibitors Warfarin Omeprazole Theophyllin Cimetidine cyclosporine Erythromycin ketoconazole Nifedipine, simvastatin Grapefruit

Reactions of drug metabolism Phase II reactions: This phase consists of conjugation reactions with an endogenous substrate, such as glucuronic acid (Glucuronidation), sulfuric acid, acetic acid, or an amino acid results in polar, usually more water-soluble compounds that are most often therapeutically inactive. Example: Chloramphinicol: Glucuronidation?? Can cause Gray-baby syndrom in neonates why?

2. Drug elimination Renal elimination of a drug: Involves three process: Glomerular filtration: Passively transport For low M.Wt drug For free drug (unbound to plasma protein) Glomerular filtration Rate = 125 ml/min

2. Drug elimination Renal elimination of a drug: Proximal tubular secretion By active transport (carrier-requiring) systems, one for anions and one for cations competition between drugs for these carriers can occur Example: Probencid

2. Drug elimination Renal elimination of a drug: Distal tubular reabsorption: The drug, (if lipid soluble, uncharged, or un-ionized) may diffuse out of the distal convoluted tubule, back into the systemic circulation Ion trapping: weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. Example: for overdoses of weak acids e.g., aspirin and phenobarbitol we give ___??____ to increase the PH of the urine and ??? For overdoses of weak bases (amphetamine), acidification of urine by ____??___________ Phenobarbitol + bicarbonate HCO3-2

Total body clearance Other route of drug clearance: The bile The lung (pulmonary) The nursing milk Sweat Saliva Tears Skin

Total body clearance CL total = CLhepatic + CLrenal + CLpulmonary + CLother

Kinetics of Continuous IV Administration After IV infusion, the plasma concentration of drug rises until it reaches a steady-state a steady-state : the rate of drug eliminated (output rate) from the body equals the rate of infusion ( input rate). At the steady-state the plasma concentration of drug remains constant.

Kinetics of Continuous IV Administration 50% of the steady-state value is achieved in one t1/2. 90% of the steady-state value is achieved in 3.3 times t1/2. The drug needs four t1/2 to reach its steady- state The steady state is directly proprtional to rate of drug infusion The steady state is inversly proprtional to the clearance rate

Fixed-dose/fixed-time regimens A B

LD = Vd x desired plasma conc Loading dose Loading dose: A drug can be injected as a single dose to achieve the desired plasma level rapidly, followed by an infusion to maintain the steady state (maintenance dose). the loading dose can be calculated as: LD = Vd x desired plasma conc F Example: lidocaine loading dose

MD = Desired plasma Conc X CL Maintenance dose Maintenance dose: Drug administered to maintain the steady state conc within the therapeutic window. MD = Desired plasma Conc X CL F

Dose adjustment Example: heart failure patient is not well controlled. Digoxin level shows subtherapeutic 0.8 mcg/L. She received 50 mcg as standard dose. Target therapeutic level is 2 mcg/L . What dose should she receive? Calculate vd= dose/conc = 50/0.8= 62.5 L Additional dose needed =Vd (C2 – C1)= 62.5 (2- 0.8) = 75 mcg The total dose needed: 50 +75 = 125 mcg

Questions A target concentration of 7.5 mg/L of theophylline is required for a 60 kg patient. What is the maintenance dose, given the following: Vd = 0.5 L/kg, Cl = 0.04 L/kg/hr,? If a drug with a 2-hour half life is given with an initial dose of 8 mcg/ml, assuming first-order kinetics elimination, how much drug will be left at 6 hours? 400 mg of a drug is administered to a patient and the drug is later measured in plasma to be 2 µg/ml. What is the apparent volume of distribution (Vd)? A drug with a half-life of 6 hours is administered by continuous intravenous infusion. How long will it take for the drug to reach 90 percent of its final steady state level?

THE END of pharmacokinetics