Pharmacokinetics Ii

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Redistribution

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a. Rate of drug distribution to tissues depends on blood flow
b. May terminate the action of some highly lipid-soluble drugs, although they remain in the body until excreted

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Biotransformation (metabolism)

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i. Occurs in various tissues→ gut, plasma, kidney, lung, brain, or liver (major site)
ii. Usually increases drug polarity and water solubility

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Metabolites in biotransformation

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iii. Metabolites may be more or less active (or toxic) than the parent compound
1. Some drugs have active metabolites
2. Prodrugs are inactive until converted to active forms
3. Reactive metabolites may causes tissue damage

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Phase I

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i. Functionalization
ii. Reactions alter and create new functional groups or cleave esters/amides to release masked functional groups
1. Oxidation
2. Reduction
3. Hydrolysis

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Phase II

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i. Conjugation
ii. Reactions couple the drug to an endogenous substrate such as an AA, acetic acid, glucuronic acid, or sulfate
iii. Attachment of these hydrophilic groups usually makes the drug more polar and less active

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Microsomal enzymes

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i. Located on smooth surface of ER, especially in the liver
ii. Catalyze oxidation, reduction, hydrolysis, and glucuronide conjugation reactions

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Cytochrome P450

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i. Major enzyme complexes for redox are cytochrome P450 and cytochrome P450 reductase
1. Families: CYP 1, 2, 3
2. Subfamilies: CYP1A, 1B, 1C
3. Members of subfamilies: CYP1A1, 1A2, 1A3

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Major isoforms of CYP

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1. CYP3A4 metabolizes the largest # of drugs in humans
2. Others→ CYP2D6, CYP2C9

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Important characteristics of CYP isoforms

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1. Potential for drug interactions
2. Activity of enzymes may be induced or inhibited
3. Genetic polymorphisms can occur

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Nonmicrosomal enzymes

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i. Responsible for most hydrolysis, many oxidation and some reduction reactions→ MAO, alcohol DH, xanthine oxidase, cholinesterase
ii. Catalyze all Phase II conjugation except glucuronidation→ acetyl-, methyl-, sulfo-, GSH-transferases
iii. Metabolic pathways may become saturated, leading to alternate metabolic pathway

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Enzyme induction

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a. Occurs when prior administration of an agent increases the total amount of enzyme
b. May be due to increased protein synthesis or substrate stabilization
c. Autoinduction can occur
d. Only microsomal enzymes can be induced

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Examples of inducing agents

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a. Drugs→ phenobarbital, phenytoin, rifampin
b. Environmental chemicals→ PAHs (tobacco smoke)

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Consequence of enzyme induction

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a. Faster rate of drug metabolism, resulting in lower drug levels

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Enzyme inhibition

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a. Occurs when one drug inhibits the metabolism of another drug
i. May be competitive or noncompetitive, reversible or irreversible

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Examples of inhibitors

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a. Competition between drugs→ ketoconazole
b. Mechanism-based inactivation→ erythromycin
c. Other covalent modifiers→ chloramphenicol, furanocoumarins in grapefruit juice

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Consequence of enzyme inhibition

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a. Slower rate of drug metabolism, resulting in higher drug levels

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Pharmacogenetics

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a. Genetic polymorphisms may contribute to inter-individual variability in drug metabolism

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Pharmacogenetics in microsomal enzymes

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i. Variante alleles affect rates of drug metabolism by CYPs
ii. Codeine, warfarin→ poor, extensive, and ultrarapid metabolizers

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Pharmacogenetics in nonmicrosomal enzymes

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i. Variant alleles affect rates of conjugation by transferases
ii. Isoniazid, hydralazine, procainamide→ slow v. fast acetylators

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Metabolism of codeine

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a. Metabolized to morphine, a more potent opioid by CYP2D6
b. Poor metabolizers may not generate enough morphine to elicit an analgesic effect
c. Ultrarapid metabolizers may develop toxicity to morphine

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Drug excretion

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a. Drugs are excreted from the body either unchanged or as metabolites
b. Most common route is through the kidney, but also biliary, pulmonary
c. Polar compounds are eliminated more efficiently than highly lipid-soluble compounds

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Renal excretion

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a. May involve one or more of the following
i. Glomerular filtration (passive)
ii. Active tubular secretion
iii. Active or passive reabsorption

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Factors influencing glomerular filtration

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i. Plasma protein binding→ only free drug is filtered
ii. Molecular size→ low molecular weight is favored
iii. Ionization→ charged molecules are filtered at slower rates than uncharged molecules

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Passive readsorption

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i. Some substances diffuse back across tubular membranes and are reabsorbed, depending on their lipid solubility and other factors

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Urinary pH influence on passive reabsorption

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1. Acidficiation→ promotes excretion of weak bases
2. Alkalinization→ promotes excretion of weak acids→ administer sodium bicarbonate

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Active tubular excretion

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i. Membrane transport systems are involved in renal excretion of some drugs
ii. Saturation of binding sites and competition for carrier proteins may occur
iii. Active secretory systems can rapidly remove protein-bound drugs from the blood

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Active tubular reabsorption

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i. Membrane transport systems may also promote reabsorption of some substances

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Clearance

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i. Theoretical volume of plasma from which a drug is removed per unit of time
ii. Depends on a drug’s Vd and degree of protein binding

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Renal clearance

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1. Can vary greatly, depending on
a. Glomerular filtration rate
b. Active tubular secretion
c. Passive diffusion

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Biliary excretion

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a. Important for excretion of some drugs and conjugated metabolites
b. Membrane transporters mediate efflux of drugs and their metabolites from the live into the bile
c. This contributes to enterohepatic recycling of some drugs

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Hepatobiliary drug transport

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a. Uptake transporters mediate drug uptake from the circulation into the liver
b. In liver, drug may undergo Phase I and/or Phase II metabolism
c. Efflux transporters mediate drug excretion
d. into bile or back into blood

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Enterohepatic recycling of drugs

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a. After a drug or its conjugate enters the intestinal lumen via bile, it passes down the gut and may be eliminated in feces
b. Some conjugates undergo bacterial hyroysis and the drug may be reabsorbed into the portal circulation
c. This can prolong the duration of action of a drug in the body

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Pulmonary excretion

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a. Volatile material, irrespective of the route of administration can be excreted via the lungs

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Sweat and saliva excretion

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a. Minor importance for most drugs

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Milk excretion

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a. Drugs ingested by a nursing mother may be found in breast milk, depending on their distribution characteristics

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First-order kinetics

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i. Constant fraction of drug present in the body is eliminated per unit time (most drugs)

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Zero-order kinetics

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i. Constant amount of drug in the body is eliminated per unit time

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Mixed-order kinetic switch

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i. If capacity for drug elimination becomes saturated at higher concentrations, kinetics may change from first order to zero order depending on dose

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Elimination half-life

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a. T ½-- time required for plasma drug concentration to decrease by one-half
b. Determined from a plot of plasma drug concentration vs. time or an equation
c. Applies only to drugs eliminated with first-order kinetics, not zero-order
d. Useful in determining dosing interval and time required to reach steady state after repeated administration of a drug (4-5 half lives)