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DRUG DISPOSITION OBJECTIVES After studying this unit, you should be able to:

DRUG DISPOSITION OBJECTIVES After studying this unit, you should be able to: 1. Describe how drugs get across membrane barriers in the body and how pH can affect this movement.

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DRUG DISPOSITION OBJECTIVES After studying this unit, you should be able to:

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  1. DRUG DISPOSITION OBJECTIVES After studying this unit, you should be able to: 1. Describe how drugs get across membrane barriers in the body and how pH can affect this movement. 2. Describe how drugs distribute among the various body compartments and state how this distribution is described quantitatively. 3. Describe how drugs are structurally altered via biotransformation processes and how these alterations affect drug behavior in the body. 4. Describe how drugs are removed from the body. 5. Describe how drug interactions can result from absorption, distribution, biotransformation, and excretion processes. 6. Describe how these processes can be manipulated in the management of drug overdose.

  2. PROTOTYPE DRUGS We will not discuss specific drugs in this section but rather some general types: 1. Organic acid drugs, e.g. those containing an ionizable carboxyl group (R-COOH). 2. Organic base drugs, e.g. those containing an ionizable amino group (R-NH2, R2NH, R3N). 3. Organic neutral non-ionizable drugs. 4. Large molecule drugs, e.g. polypeptides and proteins.

  3. I. INTRODUCTION Our objectives in drug therapeutics are to administer a drug, to get it to its site of action in sufficient quantity to exert its effect for some useful period of time, and then ultimately terminate its action and remove it from the body. What happens to the drug in this process is termed drug disposition which includes drug absorption, distribution, biotransformation, and excretion. In this section we will consider these processes qualitatively. Subsequently, Dr. Walle will discuss the quantitative description of drug disposition,i.e. pharmacokinetics. The processes involved in drug disposition are depicted schematically in the diagram below which will be referred to throughout this section.

  4. II. DRUG ABSORPTION Drug absorption is the process of getting the drug into the body; most often this is synonymous with getting the drug into the blood. A. Movement of Drugs Across Biological Membranes Movements Into (Absorption), as well as Within (Distribution, Biotransformation) and Out (Excretion) of the body involve drug moving from one compartment to another by crossing membrane barriers (a cell membrane or a layer of cells). Physical properties determine the movement of drugs across membranes. Transfer of drugs across membranes occurs by: 1. Passive transfer processes: a. Passive diffusion 1) Lipid solubility required to dissolve in membrane (a function of polar and non-polar groups) a) Polar groups (e.g. COOH, NH, OH, charged groups) increase water solubility b) Nonpolar groups (e.g. CH2, CH3, aromatic rings) - increase lipid solubility 2) Ionization (organic acids and bases) increase polarity 3) Requires concentration gradient for net transport b. Filtration 1) Molecular size 2) Requires concentration gradient for net transport

  5. II. DRUG ABSORPTION 2. Carrier mediated transfer processes a. Active transport 1) Discrete transporter proteins; finite number, therefore saturable 2) Structurally selective; competitive inhibition 3) Energy requiring; can transport against concentration gradient 4) Examples: (a) amino acid transport; amino acid analog drugs (b) P-glycoprotein; multidrug resistance (c) acid and base transport in renal tubule b.Receptor mediated endocytosis 1) Involves membrane receptors 2) Transport of large polypeptides and proteins 3) Likely to become increasingly important with the use of bioengineered proteins as drugs

  6. Transfer of small molecules across membrane barriers:

  7. Transfer of large molecules by receptor mediated endocytosis:

  8. Passive DiffusionPrinciple of Non-ionic Diffusion Only the nonionized form of a drug diffuses across the lipid membrane The more lipophilic the drug is, the faster is the diffusion 3. At equilibrium the concentration of the nonionized form is the same on both sides of the membrane

  9. pH Partition Effects If the drug is an ionizable acid or base, the concentration of total drugon each side of the membrane can be vastly different if there is a pH gradient across the membrane 1. Acid drugs tend to concentrate on the high pH side of the membrane. 2. Basic drugs tend to concentrate on the low pH side of the membrane.

  10. pH Partition Effects • The ionization tendency of a drug is indicated by its pKa. The pKa is the pH at which the drug is half ionized. (Note that the pKa does not tell you if a drug is an acid or a base; it only tells you how strongly it tends to ionize.) • pH = pKa equal concentration of ionized and nonionized (ratio 1:1) • acid drugs are increasingly ionized as pH goes up (more basic) • basic drugs are increasingly ionized as pH goes down (more acidic) • for each pH unit away from the pKa, the ratio increases tenfold • pH has no effect on neutral, nonionizable drugs)

  11. B. Absorption of Drugs from the Gastrointestinal Tract via Oral Dosing • The drug must first dissolve in the gastric and intestinal fluids. • a) The pharmaceutical preparation can affect dissolution • b) Different salt forms of a drug have different solubilities • c) Other materials present can render dissolved drug nonabsorbable

  12. Properties of the drug affect its absorption. a) Lipophilicity b) Ionization some examples: Ratio - Nonionized : Ionized Stomach Intestine Plasma pH 1.4 pH 5.4 pH 7.4 _______ _______ _______ Acidic drug (Probenecid) pKa 3.4 100 : 1 1 : 100 1:10,000 Basic drug (Amitriptyline) pKa 9.4 1 : 10 8 1 : 10 4 1:100

  13. Properties of the drug affect its absorption (cont.) For drugs with very low Nonionized : Ionized ratios (< 1 : 1000) and which are not very lipophilic absorption will be poor. There is very poor absorption of completely charged drugs, e.g. quaternary ammonium compounds. 3. Properties of the absorbing surface which affect absorption: a) area of surface b) blood circulation to absorbing surface 4. Other factors which affect absorption: a) concentration of dissolved drug b) contact time with the absorbing surface

  14. C. Absorption of Drugs Administered via Other Routes 1. Alimentary tract a. Oral mucosa - rapid absorption, small surface area (used for potent drugs to relieve anginal pain); avoids immediate exposure to liver b. Rectal mucosa - suppository dosage; alternate route for nauseated patient; only ca. 50% passes immediately through the liver 2. Parenteral routes - bypassing G.I. tract and immediate exposure to the liver a. Routes which still entail an absorption process: (absorption rate can vary depending upon the vehicle) 1) subcutaneous 2) intramuscular b. Routes which bypass the absorption process: 1) intravenous 2) intraarterial 3) intrathecal (into the spinal subarachnoid space) 3. Pulmonary endothelium (volatile anesthetics, aerosols) 4. Skin a. few drugs readily penetrate the intact skin b. penetration can be enhanced by using oily vehicle c. controlled-release topical patches e.g. for the highly potent antihypertensive drug clonidine 5. Mucous membranes (systemic absorption of drugs used for local effects)

  15. DRUG DISTRIBUTION (see the general diagram on page 2) Tissue distribution of drugs is usually not uniform throughout the body; drug concentration at the site of action determines the pharmacologic effect. A. Differential Distribution of Drugs into Different Body Compartments An example - Concentrations of the antihypertensive drug propranolol in tissues 3 hr after an i.v. dose (Walle, etal.) Blood 0.13 µg/g Aorta 0.18 µg/g Muscle 0.38 µg/g Heart 0.60 µg/g Lung 8.29 µg/g Liver 0.49 µg/g Brain 1.64 µg/g How can we examine drug distribution in man when only blood concentrations can readily be measured?

  16. Apparent Volume of Distribution (Vd) - the volume the drug appears to be distributed in, at the same concentration as in blood:Vd = Amount of Drug in the Body___ Concentration of Drug in the BloodAn analogy: Example - Give 70 mg of drug to a 70 kg (70 liters volume) patient. If the drug is evenly distributed in blood and all tissues, then the blood concentration = 70 mg./70 liters = 1 mg/l. Vd = 70 mg / 1 mg/l. = 70 liters = the actual volume

  17. Example (continued): If the drug is highly bound in certain tissues (analogy - stuck to bottom of container), less is in the blood leading to a lower blood concentration and a higher Vd. Vd = 70 mg / 0.1 mg/l. = 700 liters = a larger apparent volume If (in this example) the blood concentration (Cb) is < 1 mg./l., then the drug is distributed into tissues and preferentially bound there. If (in this example) Cb > 1 mg/l, the drug is distributed into a smaller volume than the total body volume (e.g. a drug might distribute only into body water). For perspective - some typical volumes for a “normal” 70 kg person: Body volume 70 liters Body water 41 liters Extracellular water 12 liters Whole blood 6 liters Plasma 3 liters Of what use is the Vd information? 1. Quantitative representation of distribution - Is the drug mainly in tissues or in blood. 2. Estimation of amount of drug in body and the proportion readily available for therapeutic manipulation. 3. The larger the Vd , the longer the drug will stay in the body.

  18. Distribution of Drugs within the Blood (refer to general diagram on page 2) 1. Drug is present both free in solution and bound to plasma proteins; protein binding is a reversible process. An equilibrium is established which depends upon the affinity of the drug for the binding sites. a. Only free drug can cross membranes to enter other tissues b. Only free drug can bind to receptors. Thus, a change in free drug blood concentration can lead to a transient change inpharmacological response and in the Vd. Note - most blood level determinations for drugs measure both bound and unbound. 2. The free drug concentration is determined by binding to plasma proteins. Acidic drugs bind mainly to albumin. Basic drugs bind mainly to 1-acidglycoprotein.Lipophilicity also important. 3. There are a finite number of binding sites on these proteins. Thus, saturation as well as competition can occur.

  19. Distribution of Drugs within the Blood (cont.) 4. Historically, textbooks have emphasized plasma protein binding displacement interactions as clinically significant. Most such clinical effects are now recognized as due primarily to other interactions, e.g., inhibition of metabolism. 5. Binding interactions likely to be clinically significant only in few cases, particularly where: a. Drug is very highly bound > 90% b. Drug has very low therapeutic index (toxic conc./therap. conc.) c. Drug has a low hepatic extraction d. Drug is given intravenously. C. Distribution of Drugs in Other Tissues 1. Binding can be functional (i.e. to receptors) or nonfunctional sequestration to tissue proteins. 2. Binding to tissue proteins is reversible, but may be rate limiting in elimination. Highly lipophilic drugs tend to be highly bound. 3. Intracellular Distribution - pH partition between plasma (pH 7.4) and intracellular space (pH 7.0) is small but favors movement of basic drugs into cells. 4. Basic drugs can also accumulate at more acidic intracellular sites (e.g. lysosomes, storage granules).

  20. C. Distribution of Drugs in Other Tissues (cont.) • Fat as a storage depot - highly lipid soluble drugs accumulate in adipose tissue (important for toxic chemicals, e.g. polychlorinated organics). • Time course of tissue distribution (drug “redistribution”) - Distribution equilibrium occurs in stages due to differences in perfusion of different tissues: a. Highly vascularized tissues (e.g. brain, visceral organs) equilibrate first (e.g. for the short acting anesthetic, thiopental, peak concentration in brain is reached 30 sec after intravenous dose.) b. Less vascularized tissues (e.g. muscle, skin) equilibrate more slowly (for thiopental, 15 - 30 min). c. Poorly vascularized tissues (adipose, bone) equilibrate last (may require several hours). d. Some drug effects may be terminated by redistribution rather than actual elimination (biotransformation or excretion) of the drug.

  21. D. Distribution Across Some Particular Barriers 1. Blood Brain Barrier a. There are tight junctions between endothelial cells of brain capillaries and few transendothelial channels - thus, passage of drugs from the blood into the central nervous system is severely restricted. b. Drugs cross the blood brain barrier by: • Passive diffusion - highly lipid soluble drugs cross rapidly (peak concentration reached in minutes). Very polar, highly water soluble drugs do not cross at all. • Active transport - e.g. transport of amino acid type of drugs (methyldopa, L-dopa) iii) Endocytosis - engineered chimeric proteins can exploit natural receptors to transport proteins into CNS (experimental Alzheimers disease therapy uses transferrin receptor antibody conjugated to nerve growth factor).

  22. 1. Blood Brain Barrier (cont.) • Strategies for delivery of highly water soluble drugs: • i) Invasive - intrathecal or intraventricular injection. • ii) Transient disruption of the barrier with mannitol. • iii) Prodrugs* - metabolized to active form within the CNS. • (*definition of prodrug – an inactive form of a drug that is converted to active form in the body. • Prodrugs are used to achieve more desirable absorption/distribution when the actual active form is deficient in desired properties.

  23. 2. Placental "Barrier" a. Exhibits all modes of transfer of molecules across membranes. Passive diffusion due to lipid solubility is probably most important. Thus, there is no protective barrier. b. Drug exposure is especially risky to the fetus due to susceptibility to teratogenic effects in early development. Metabolites can accumulate in the fetus due to lower lipid solubility of the metabolites compared to parent drug.

  24. IV. BIOTRANSFORMATION (DRUG METABOLISM) • Biotransformation leads to structural alteration of the drug molecule by the action of a variety of enzymes. This alteration generallyfacilitates excretion of lipid soluble drugs by making them more water soluble A. Drugs often undergo two step ( “biphasic”) metabolism, e.g. 1. Phase I biotransformation reactionschemically modify the drug via oxidation, reduction, hydrolysis, etc. which, in addition to changing the physical properties of the molecule (e.g. water solubility), results in: a. Inactivation (“detoxification”) of the drug. A portion of the chemical structure, essential to the pharmacological effect, has been altered. b. Conversion of active drug to active drug metabolite. A portion of the chemical structure, not essential to the pharmacological effect, has been altered.

  25. 1. Phase I biotransformation (cont.) • c. Conversion of inactive drug compound (e.g. prodrug) to active drug. • e.g. Enalapril (an inactive ester with good absorption properties) is hydrolyzed • to a biologically active carboxylic acid metabolite. • Generation of a chemically reactive metabolite (reactive intermediate). • e.g. The anesthetic halothane is oxidized to trifluoroacetyl chloride which • can subsequently react chemically to form a covalent bond to proteins. Phase I reactions yield metabolic products which are generally more polar than the parent ug and are therefore more easily excreted.

  26. 2.Phase II biotransformation reactions add a conjugating group to the drug molecule which (almost always) results in: • a. Pharmacologically inactive metabolites. • b. Highly ionized, polar, water soluble metabolites. Examples: acetaminophen (a weak acid with pKa 10) yields more acidic sulfate and glucuronide conjugates

  27. 2. Phase II biotransformation (cont.) c. Exception: Acetylation (e.g. of sulfonamides) yields less soluble metabolites:

  28. 3. Many drugs undergo both Phase I and Phase II metabolism, e.g. propranol D = distribution coefficient between organic and aqueous phases, a measure of lipophilicity.

  29. B. Drug Metabolizing Enzymes Metabolic sites a. Liver (most important site of drug metabolism) - factors affecting hepatic clearance of drugs include: i. activity of the drug metabolizing enzymes ii. hepatic blood flowIn some cases, hepatic clearance can be sufficiently high to remove most of the drug from the blood passing through the liver. This effect is called “presystemic” or “first-pass hepatic elimination.”

  30. Definition: “Extraction Ratio” b. Drug metabolism also occurs in many other tissues (e.g. intestine, lung, kidney)

  31. 2. Liver microsomal metabolism (Microsomes are isolated smooth endoplasmic reticulum) The smooth endoplasmic reticulum contains two particularly important drug metabolizing enzyme systems: the Cytochrome P450 (CYP) complex and the UDP-glucuronyl transferase system. a.Cytochrome P-450(CYP) complex: i. iron-heme monoxygenase enzyme with associated NADPH - CYP oxidoreductase; require molecular oxygen and NADPH ii. large number of CYP isoenzymes; gene superfamily iii. wide range of substrates - isoenzymes oxidize particular structural types iv. CYP’s also involved in endogenous metabolism e.g. steroids Net reaction: Drug - H + O2 + 2NADPH  Drug - OH + H2O + 2NADP+ b. UDP-glucuronyl transferase - forms glucuronic acid conjugates (See p. 13)

  32. 3. Nonmicrosomal enzymes - in liver, other tissues and in plasma • a. Phenolsulfotransferases - form sulfate conjugates (See p.13) • b. Alcohol dehydrogenase • c. Mitochondrial monoamine oxidase (MAO) • d. Esterases • e. Amidases

  33. C. Significance of Biotransformation 1. Biotransformation is responsible for termination of pharmacological effects of lipophilic drugs.2. Large variability in biotransformation yields large variability in drug response. D. Variability in Biotransformation 1. Variability Among Individuals a. Genetic differences i. Cytochrome P-450 (CYP) isoenzymes Drug oxidations - Bimodal distribution:

  34. D. Variability in Biotransformation (cont.) 1. Variability Among Individuals a. Genetic differences There are multiple cases of known genetic polymorphism with respect to CYP genes for drug metabolizing enzymes. The classical test for CYP2D6 phenotype is the debrisoquin polymorphism test wherein the ratio of parent drug to metabolite is determined in patients following a test dose of debrisoquin. Gene chip tests are now available to determine genotype of multiple CYP genes. Different population groups exhibit different genetic distributions. ii. Some other drug metabolizing enzymes are known to exhibit genetic polymorphism: a) N-acetyl transferase; Bimodal or trimodal distribution: b) Pseudocholinesterase (hydrolysis of muscle relaxant succinylcholine) - Trimodal distribution • b. Age differences • i. Biotransformation enzyme activities low in neonates. Newborns are often deficient in glucuronidation ability. • ii. Elderly are heterogeneous due to different rates of deterioration of enzyme and • elimination systems. No blanket statement can be made regarding dosage adjustment

  35. D. Variability in Biotransformation (cont.) 1. Variability Among Individuals (cont.) c. Sex differences. Females metabolize many drugs slower than males. Metabolism rate of some drugs is correlated with testosterone levels. d. Pathology. e.g. liver disease e. Species differences - important in new drug development. • 2. Variability Within A Given Individual • a. Enzyme induction • i. Stimulation of metabolism by other substances (very common). Smoking, alcohol, pesticides, other drugs, diet (brussel sprouts, charcoal-broiled meat, high protein) • ii. Stimulation of drug's own metabolism (autoinduction) - Blood levels fall during • chronic therapy (tolerance). Induction is a slow process. • b. Enzyme inhibition • One drug inhibits the metabolism of another via competition at the same site of an enzyme.

  36. 2. Variability Within A Given Individual (cont.) b. Enzyme inhibition (cont.) Examples: Cimetidine (anti-ulcer) inhibits the metabolism of warfarin (anticoagulant). Some antifungals and antibiotics inhibit CYP3A4 which oxidizes terfenadine leading to excessive blood levels and arrhythmias. Fluoxetine (Prozac) is an inhibitor of microsomal oxidation (CYP2D6). Grapefruit juice inhibits metabolism of cyclosporin.

  37. 3.Variability with Regard to the Drug Itself - Differential Metabolism of Optical Isomers (Enantiomers). e.g. The biologically inactive (R)-ibuprofen is converted to the active (S)-form via metabolic conversion to a coenzyme A ester. Many drugs are now marketed as single enantiomers (e.g., Nexium is single enantiomer of Prilosec).

  38. V. DRUG EXCRETION Elimination of drug and metabolites from the body - since excreta (e.g. urine) are more “waterlike” than the body as a whole, water soluble forms of the drug are required.A. Renal Excretion

  39. A. Renal Excretion (cont.) 1. Glomerular filtration - Only unbound (free) drug in blood. 2. Proximal tubular transport - secretion into urine. a. Two systems involved: i. one for organic acids ii. one for organic bases b. Competition for transport mechanism. Example. Probenecid and penicillin, to retain penicillin in the body 3. Distal tubule. a. Reabsorption by passive diffusion b. Can be modulated by pH of urine i. Enhance excretion of acids by increasing urine pH . ii. Enhance excretion of bases by decreasing urine pH.

  40. B.Biliary Excretion 1. Active transport of polar molecules, especially anionic (i.e. negatively charged) molecules, into bile. 2. Drug metabolites eliminated by biliary excretion tend to be comparatively large (molecular weight > 300) molecules; glucuronic acid conjugates in particular. 3. Enterohepatic recirculation a. tends to prolong duration of drug in the body b. can be interrupted by diarrhea, antibiotic therapy Enterohepatic recirculation

  41. SUMMARY OF CLINICAL SIGNIFICANCE OF DRUG DISPOSITION EFFECTSA. Some clinically significant drug disposition effects which can lead to variability in drug blood levels and therefore variability in pharmacological response: 1. Binding to materials in GI tract (reduces absorption). 2. Plasma protein binding (protein concentration, competition effects). 3. Biotransformation (induction, inhibition, genetic variation). 4. Renal active transport competition. 5. Hepatic and renal blood flow effects. 6. Urinary pH effects. 7. Hepatic and renal disease effects. 8. Alterations of gut flora.

  42. B. Treatment of drug overdose 1. Supportive treatment - treating the patient, not the poison. 2. Antidotal treatment - available for relatively few drugs. 3. Treatment based on altering drug disposition: a. Retard absorption by i. emesis ii. gastric lavage iii. charcoal iv. catharsis b. Alter distribution - little can be done c. Alter biotransformation - retard formation of toxic metabolite (to be discussed in Toxicology section). d. Enhance urinary excretion i. diuresis ii. alter urine pH Acidify urine (ammonium chloride) to enhance excretion of basic drugs. Alkalinize urine (sodium bicarbonate) to enhance excretion of acid drugs.

  43. REVIEW QUESTIONS: ___1. Active transport of an acid drug from blood to urine in the proximal tubule a. may be increased by lowering the pH of the urine b. may be inhibited by administering another acid drug c. decreases the systemic clearance compared to a drug which is not actively transported d. increases the elimination half life compared to a drug which is not actively transported e. increases the apparent volume of distribution compared to a drug which is not actively transported. ___2. Biotransformation of a drug most generally leads to a. a decrease in the pKa b. a decrease in water solubility c. a decrease in molecular weight d. a decrease in biological activity. e. a decrease in the duration of the drug in the body ___3. A drug of structure CH3(CH2)4CH(CH3)-NH2 , pKa 9.4, would be, a. predominantly in the nonionized form in pH 1.4 gastric juice b. more than half ionized in pH 7.4 plasma c. less than half ionized in pH 5.4 urine d. concentrated more in pH 8.4 urine as compared to pH 5.4 urine e. nonabsorbable via the gastrointestinal tract. ___4. A patient on a daily dose of drug A which is primarily eliminated by Cytochrome P450 (CYP) mediated metabolism is started on drug B which is known to induce synthesis of P450 (CYP) enzymes. This combination is likely to lead to a. an increased drug effect from drug A b. a decreased drug effect from drug A c. a decreased effect from drug B compared to the effect in the absence of A d. either (a) or no interaction depending upon the P450 (CYP) isoenzymes involved e. either (b) or no interaction depending upon the P450 (CYP) isoenzymes involved

  44. ___5. A patient on chronic therapy with an anticoagulant drug eliminated by P450 (CYP) oxidation is started on therapy with an antiulcer medication known to inhibit P450 (CYP) oxidative metabolism. The likely result is a. a need to increase the dose of anticoagulant b. a reduced antiulcer effect compared to patients not on an anticoagulant c. an excessive anticoagulant effect d. a shorter half life for the anticoagulant e. a lower than normal dose of the antiulcer medication since it inhibits its own metabolism. ___6. Urinary excretion of a basic drug could be a. increased by aspiration of gastric juice b. increased by raising the pH of the urine c. increased by inhibiting the proximal tubular active transport of bases from blood to urine d. increased by lowering the pH of the liver interstitial fluid e. none of the above ___7. One hundred percent of an oral dose of drug X is excreted within 24 hours as metabolites in the urine. Drug X a. has a bioavailability of 100% b. is extensively metabolized on its first pass through the liver c. is completely absorbed from the gastrointestinal tract d. is likely to undergo enterohepatic recirculation e. has a high apparent volume of distribution ___8. The blood-brain barrier a. blocks passive diffusion of lipid soluble compounds into the central nervous system (CNS) b. allows passage of some polar compounds into the CNS by active transport c. allows drug entry to the CNS by metabolizing a prodrug to its active form d. passes only unbound form of drug into the CNS by filtration e. all of the above

  45. ___9. Which of the following are required to get net transfer of a drug across a membrane barrier by passive diffusion? a. a higher concentration of total drug on one side of the membrane b. a higher concentration of nonionized drug on one side of the membrane c. an ionizable group on the drug molecule d. a drug carrier protein in the membrane e. all of the above ___10. Since phenytoin is less bound to plasma proteins in the uremic patient, the dose needed to achieve therapeutic effect would be expected to be: a. higher than in the normal patient b. the same as in the normal patient c. lower than in the normal patient d. lower or the same as the normal patient dependent upon whether or not the patient was a slow oxidizer phenotype e. higher or the same as the normal patient dependent upon whether or not the patient was a slow oxidizer phenotype

  46. ANSWERS TO REVIEW QUESTIONS1. b. 6. e.2. e. 7. c.3. b. 8. b.4. e. 9. b.5. c. 10. c.

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