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pharmacology

Neonatal Pharmacology and Pharmacokinetics


Pamela D. Reiter, PharmD, BCPS*

This issue of NeoReviews contains an overview of the essentials of neonatal pharmacology. This will be followed by two more pharmacologic reviews next month. Next year, we hope to have such reviews as a regular feature for each issue and trust that these will prove valuable to our readers.
Alistair G.S. Philip, MD, FRCP(E) Associate Editor, NeoReviews

Objectives
After completing this article, readers should be able to: 1. Summarize the impact of gestational age, postnatal age, and disease state on drug absorption, distribution, metabolism, and elimination. 2. Describe rst-order, one-compartment pharmacokinetics and calculate kinetic parameters. 3. Describe zero-order or saturation kinetics. 4. Characterize common pharmacodynamic models.

Introduction
There are important differences among the preterm neonate, term neonate, and young infant in terms of drug disposition (absorption, distribution, metabolism, and elimination). Variables such as gestational age, body composition, postnatal age, concomitant drug therapy, acidemia/hypoxemia, and end-organ perfusion may affect and complicate drug therapy. Additionally, developmental issues pertain to drug-receptor interactions, receptor number, receptor afnity, and receptor regulation and modulation. The neonate is in a rapid and continuous state of maturation, which can inuence signicantly the therapeutic and toxic effects of drug therapy. Our understanding of the age- and disease-related differences in the preterm neonate continues to advance through detailed clinical pharmacokinetic and pharmacodynamic evaluations. The purpose of this article is to: 1) explore the differences in drug disposition for the preterm infant and consider how these differences affect drug therapy regimens, 2) review common pharmacokinetic principles as they relate to clinical therapeutic drug monitoring, and 3) examine common pharmacodynamic models.

Factors That Modify Drug Kinetics and Dynamics


Drug Absorption
Absorption, the rst of four major steps involved with drug disposition, refers to the translocation of drug from the site of administration into the systemic circulation. Drugs administered intravascularly (intravenous or intra-arterial) have rapid and complete bioavailability. Drugs administered extravascularly (oral, rectal, inhalation, topical, intramuscular) must cross multiple membranes to reach the target site of action. This translocation process can be affected by a variety of age-dependent factors. The primary mechanism of drug absorption is passive diffusion of neutral (unionized) molecules through lipophilic membranes into the systemic circulation. Therefore, the environmental pH at the site of absorption is important. For orally administered drugs, bioavailability can be inuenced by gastric pH, gastric emptying time, bacterial colonization, bile acid production, and gastrointestinal (GI) perfusion. Although the complete
*Neonatal Intensive Care, The University of Colorado Hospital, Denver, CO. NeoReviews Vol.3 No.11 November 2002 e229

pharmacology pharmacology & pharmacokinetics

gastric acid production prole of the preterm neonate remains controversial, most agree that infants younger than 32 weeks gestation have a delayed or attenuated ability to produce acid until after 2 to 3 weeks following birth. The term relative gastric achlorhydria has been used to explain the difference in oral drug absorption between preterm and term infants in which weakly basic drugs (penicillin, ampicillin, erythromycin) remain in the unionized state and are readily absorbed, and acidic drugs (phenobarbital, phenytoin) become ionized and are poorly absorbed. Although gestational and postnatal ages of the infant are important contributing factors to gastric acid secretion, perhaps the most important factor is the presence of enteral feedings, which reduce the gastric pH. A second age-related factor that affects oral drug absorption is gastric emptying time. Transit time is delayed (up to 6 to 8 h) in the preterm infant, resulting in a delayed peak serum drug concentration. Lastly, the activity and concentration of GI enzymes, bile salts, and bacterial organisms are different in the preterm neonate and may reduce the absorption of fat-soluble vitamins and inuence the fate of conjugated forms of drugs. Despite these known differences in neonatal GI maturation processes, tangible clinical signicance is nominal because the oral route of medication delivery frequently is delayed until hemodynamic stability and enteral feeding tolerance is attained. Intramuscular and subcutaneous drug absorption is reduced in the preterm infant due to lower regional blood ow and reservoir mass. Drugs that are lipophilic diffuse rapidly into capillaries, yet they must maintain a degree of hydrophilicity at physiologic pH to prevent precipitation at the injection site. In general, these routes of drug administration are used rarely in the neonate except for drugs such as vitamin K, aminoglycosides, and erythropoietin. Percutaneous drug absorption is an often overlooked cause of serious inadvertent systemic toxicity. In contrast to the fully intact skin of a term infant at birth, the preterm infant lacks a mature layer of stratum corneum, has a high degree of skin hydration, and has a higher ratio of surface area per kilogram of weight. These elements make the preterm infants skin an ideal site for drug absorption. Transdermal drug toxicities have been reported in the literature (boric acid, hexachlorophene, aminoglycosides, alcohol, and corticosteroids), but the topical route also has been explored as a method of delivering therapeutic doses of medications to preterm infants. Both theophylline and caffeine have been administered successfully via topical gel, with achievement of therapeutic serum drug concentrations. However, transe230 NeoReviews Vol.3 No.11 November 2002

dermal drug delivery is not used in clinical practice because the skin rapidly matures by 3 weeks after birth to that of a term infant. Rectal drug absorption is affected by many of the factors mentioned previously, but it also depends on the physical position of the drug within the rectum. Drugs placed in the superior aspect of the rectum are subject to hepatic rst-pass effect (and reduced systemic bioavailability) because the superior rectal vein drains into the portal vein via the inferior mesenteric vein. Drugs placed into the lower rectum initially bypass the liver because the lower and middle rectal veins drain directly into the systemic circulation via the inferior vena cava.

Drug Distribution
Distribution refers to the process of drug movement through various body compartments, including organs, uids, tissue, fat, and muscle. The movement depends on pH, size and composition of the compartment, protein binding, membrane permeability, and hemodynamic factors, such as cardiac output. Neonatal growth is associated with marked changes in body composition. The percentage of total body water decreases from 85% at 24 weeks gestation to 75% at term; in that same time frame, fat tissue increases from 1% to 16%. Intrauterine environment and fetal disease also may affect body composition. Infants born to women who have diabetes often have large fat stores, and infants who have intrauterine growth retardation may have reduced stores. These differences in body composition directly affect the dose (mg/kg) of drug required to effect a response (see pharmacokinetic section). Protein binding has a profound effect on drug distribution, clearance, and eventual pharmacologic activity. Only unbound, or free drug, is pharmacologically active. The preterm infant has both quantitative and qualitative differences in protein binding. Important factors in preterm infants include lower concentrations of binding proteins (albumin, lipoproteins, alpha-1-acid glycoprotein, and beta globulins); the presence of fetal albumin, which has a decreased afnity for binding drug; a lower plasma pH, which reduces protein binding of acidic drugs; and the presence of endogenous protein binding competitors (bilirubin, free fatty acids). When protein binding is decreased, the volume of distribution is increased. Drugs that have an increased volume of distribution require a larger mg/kg dose to attain the same total serum concentration. However, in the face of reduced binding, for a given total serum concentration, there is a higher free fraction. This increased free fraction may result in an exaggerated therapeutic or toxic effect.

pharmacology pharmacology & pharmacokinetics

Table 1.

Comparative Protein Binding of Selected Drugs Used in Neonatal Medicine


Percent Protein Bound Drug Ampicillin Caffeine Diazepam Digoxin Lidocaine Indomethacin Morphine Phenobarbital Phenytoin Theophylline Vancomycin Neonate 7% to 10% 25% 84% to 86% 14% to 26% 20% 95% to 98% 18% to 22% 20% to 25% 70% to 80% 36% to 50% 36% Infant 10% to 12% 98%

31% 28% to 36% 80%

Competition for protein binding sites by endogenous molecules may displace bound drug and result in increased free fraction with intensied drug effect. However, the intensied pharmacologic effect may only be transient because just as the free fraction represents active drug, it is only free drug that is available for excretion. Thus, once steady state is achieved, the net result is decreased concentration of total drug accompanied by an unchanged free concentration. Clinically signicant protein binding displacement reactions occur when a drug is more than 80% bound and the clearance is bindingsensitive. These differences in protein binding underscore the importance of measuring both total and free serum drug concentrations in the neonate. Selected drugs for which protein binding and distribution are altered in the neonate are listed in Table 1. Lastly, certain neonatal conditions, such as pulmonary hypertension, hypoplastic left heart, and patent ductus arteriosus, may alter the drug distribution by preventing its movement to the site of action that ultimately affects drug activity.

Drug Metabolism
Many drugs require biotransformation into a more water-soluble, polar compound to facilitate elimination. Biotransformation takes place in a variety of organs (plasma, skin, lungs, adrenal, intestine, and kidney), but the majority occurs in the liver via phase I or phase II reactions to create a pharmacologically weaker or inactive compound. Some drugs, however, may be transformed into active metabolites or intermediates, such as theophylline to caffeine. Still others are pharmacologically inactive parent compounds (or prodrugs) that require

biotransformation to their active moiety (eg, chloramphenicol succinate, cefuroxime axetil, fosphenytoin). The effect of infant maturation on the biotransformation of drugs is difAdult cult to predict based solely on age because some metabolic pathways 18% to 30% 30% to 40% may be induced, and some drugs may 94% to 99% be forced to use alternate pathways 23% to 40% that have different clearance rates. In 70% general, biotransformation processes 90% to 95% are reduced in the preterm infant due 33% to 37% 45% to 50% to a reduction in cellular uptake of 89% to 93% drug, lower hepatic enzyme capacity, 50% to 65% decreased hepatic blood ow, and 50% to 56% reduced biliary excretion. Before biotransformation even begins, the rst step is uptake of drug into the hepatocyte by acceptor proteins. Preterm infants have lower and sometimes absent acceptor protein concentrations, resulting in impaired clearance of capacitylimited drugs (drugs that have low intrinsic clearance). Concentration of these acceptor proteins gradually increases during the rst 10 days of postnatal life. Once a drug enters the hepatocyte, it is transformed by either phase I or phase II reactions. Commonly, drugs undergo phase I reactions followed by phase II reactions. Phase I reactions have been called preparatory reactions and include oxidation, reduction, hydrolysis, and hydroxylation. These reactions allow a drug to be processed more readily by phase II reactions (glucuronidation, sulfation, acetylation, and methylation). Probably the most studied enzyme system is the hepatic cytochrome P-450 mixedfunction oxidase system. Selected isoenzymes within the P-450 enzyme family and correlating substrates are listed in Table 2. Understanding which P-450 isoenzyme is responsible for the metabolism of a drug is very useful when predicting drug interactions caused by either inhibition or induction of selective isoenzymes. Most phase I enzymes are present at birth, even in the extremely preterm infant. However, the titers of these enzymes vary in activity and can be affected by prenatal inducing agents (eg, maternal phenobarbital, antiretrovirals, and corticosteroids). The maturation of each metabolic pathway is illustrated in Figure 1. Disease-specic conditions, such as decreased cardiac output, decreased liver perfusion, liver congestion, or hypoxia, may reduce hepatic enzymatic activity further and result in lower clearance rates of selected drugs. Unless proactive changes in drug therapy regimens are instituted, reduced
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Selected Cytochrome P-450 Isoenzymes and Corresponding Substrates


Table 2.

CYP1A2 Acetaminophen Caffeine Theophylline CYP2C9 Ibuprofen Phenytoin CYP2C19 Diazepam Omeprazole

CPY3A4 Alfentanil Carbamazepine Cisapride Erythromycin Fluconazole Itraconazole Ketoconazole Lidocaine Nifedipine Midazolam Nifedipine

in the term infant, but the anatomic and functional immaturity of the premature kidney may result in lower GFR rates, even at corrected ages of up to 1 to 2 years. Tubular secretion and reabsorption rates are approximately 20% to 30% of adult values at birth and, despite a doubling by the rst week of age, may take up to 6 months to mature completely. Drugs that depend on tubular secretion for elimination (eg, furosemide, penicillins, morphine) demonstrate decreased clearance. Ultimately, the amount of drug ltered by the kidney depends on the functional capacity of the glomerulus, renal blood ow, and the extent of drug-protein binding.

Basic Principles of Pharmacokinetics


Clinical pharmacokinetics has been used for more than 20 years as a mathematical description of the processes in the body that alter drug concentrations. Combined with an appreciation of disease state and age-related processes that inuence the disposition of drugs, kinetic concepts can be used in the neonatal population to maximize efcacy and minimize toxicity of medications that have a narrow therapeutic range. Key pharmacokinetic concepts include compartmental modeling, elimination rate constant, volume of distribution, half-life, and clearance.

biotransformation and clearance lead to drug accumulation and an exaggerated pharmacologic effect.

Renal Elimination
Renal elimination of drugs involves glomerular ltration (GFR), tubular secretion, and tubular reabsorption, all of which are depressed in the preterm neonate. At birth, glomerular function is more developed and matures faster than tubular function (Fig 1). The primary factors involved in maturation of renal function are gestational age, renal vascular resistance, and renal blood ow. Analogous to hepatic enzyme function, postnatal renal function can be affected by prenatal exposure to certain drugs such as betamethasone and indomethacin. Betamethasone can increase GFR through an increase in ltration fraction; indomethacin may reduce GFR through inhibition of prostaglandin synthesis followed by an increase in renal vascular resistance and eventual reduction in renal blood ow. The effect of postnatal age on GFR depends on gestational age. GFR is directly proportional to gestational age, but this linear relationship is not evident until 34 weeks gestation. Term infants can double their GFR within the rst 2 weeks after birth in response to a decrease in renal vascular resistance and an increase in cardiac output to the kidney and subsequent increase in renal blood ow. Maturation of GFR in the preterm infant is not as impressive, perhaps because of incomplete nephrogenesis. Initial GFR values in the term infant are higher at 2 to 4 mL/min than in the preterm infant at 0.7 to 0.8 mL/min (0.5% of adult values). Adult values are reached at approximately 2.5 to 5 months after birth
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Comparmental Modeling
Compartmental models are used as abstract representations of the body to describe how a drug distributes. Typical compartments include central compartments that represent highly perfused tissues (eg, heart, liver, lungs, kidney, and blood) and peripheral compartments that represent distal tissues such as fat, muscle, and cerebrospinal uid. Graphically, compartmental models may be illustrated by changes in the slope of the elimination curve. In general, each slope of a line represents drug distribution and elimination of a specic compartment. Figure 2 demonstrates a compartmental model that has a brief and noncontributory alpha-phase (A) and a longer, more signicant beta-phase (B). The one-compartment model is the model used most frequently in clinical practice. It assumes that a drug distributes instantly to all body tissues and uids. With this model, it also is assumed that elimination is described by a rst-order process. In reality, few drugs are onecompartment systems, but if the peripheral compartments of a drug do not contribute signicantly to drug behavior, a one-compartment model can be used to describe the drugs kinetics. Drugs that are polar and do not distribute into extravascular tissues, such as aminoglycosides, generally are described by a onecompartment model in which the distribution phase

pharmacology pharmacology & pharmacokinetics

(alpha-phase) is very short (15 to 20 min) and the metabolism and elimination phases (beta-phase or terminal phase) are much slower. Drugs that are lipophilic (benzodiazepines) or have extensive tissue or intracellular uptake may be described better by a more complex, multicompartmental model. Digoxin is described best by a twocompartment model and has a long distribution phase of 4 to 6 hours (Fig 2B). In clinical practice, it is important to know the compartmental model and distribution time of a given drug to avoid obtaining a plasma drug concentration until distribution is complete and a pseudoequilibrium between central and peripheral compartments is achieved.

Table 3.

Simplied, First-order, One-compartment Pharmacokinetic Equations


Ln C1-LnC2 Ln (C1/C2) or T1-T2 T1-T2 drug concentration at time T1 C2 drug concentration at time T2 e
Ke(T)

Equation 1 Elimination Rate (Ke) C1 Equation 2 Cmax C C T Equation 3 Prediction of Plasma Concentration at Time (t) C0e kt C0 peak drug concentration or concentration at an earlier time Equation 4 Volume of Distribution (Vd; L/kg) Dose (mg) after dose mg/L (C0) or VD Dose (mg/kg) (Peak Trough) Equation 5 Loading dose (mg/kg) Equation 6 desired plasma concentration (mg/L) Vd (L/kg) drug concentration immediately drug concentration at later time and time when C was obtained time of Cmax

Elimination Rate Constant

With rst-order elimination, the Half-life (t12; h) 0.693(Vd) Cls or 0.693 Ke (hr-1) amount of drug eliminated per Equation 7 unit of time increases as the Clearance (Cls; L/kg/h) Vd (L/kg) Ke (hr-1) amount of drug in the body inEquation 8 creases, but the fraction of the drug eliminated remains the (Dose dosing interval) Steady-state concentration (Css) same. For rst-order eliminaCls tion, the natural log of plasma concentration versus time plot is linear (Fig 3). In contrast, zerodrugs (eg, phenytoin) may display zero-order kinetics order elimination (also known as saturation kinetics or within the normal dosing and therapeutic range such that Michaelis-Menten kinetics) occurs when a constant fraca small change in dose results in a disproportionate change tion of drug is removed per unit of time, regardless of the in serum drug concentration. With rst-order kinetics, once amount of drug in the body. Another type of nonlinear two plasma drug concentrations are known, the elimination kinetics can occur when a drug that has low intrinsic rate constant (ke) can be calculated (equation 1, Table 3). clearance begins to saturate drug-protein binding sites. Through mathematical manipulations, a simple equation As the fraction of unbound drug in the bloodstream can be derived to predict drug plasma concentrations at any increases, the amount of drug available for clearance also time after a given dose of a drug that exhibits rst-order increases (Fig 4), leading to a lower-than-expected kinetics (equations 2 and 3, Table 3). change in total drug concentration with a proportional change in drug dose. The free drug concentration, howVolume of Distribution ever, changes proportionally with a change in dose. The apparent volume of distribution (Vd) is a proporFortunately, most drugs used in neonatology display tionality constant that relates the amount of drug in the rst-order kinetics, but some drugs may switch from body to the serum concentration (equation 4, Table 3). rst-order to zero-order when serum concentrations are Because the body composition of neonates is predomiabove the therapeutic range (eg, theophylline). Other
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nately water, hydrophilic drugs have higher Vd values and lipophilic drugs have lower Vd values compared with older infants. If a drug distributes extensively in tissues (eg, digoxin), the Vd calculated from plasma concentrations will be much larger than the actual physiologic volume in which it distributes. Vd is a useful parameter when calculating a patient-specic loading dose (equation 5, Table 3).

Applying Pharmacokinetics
Kinetic principles can be applied to a number of drugs used in the neonate, assuming a relationship exists between plasma drug concentration and pharmacologic effect/toxicity. Computer programs are available to aid in the calculation, interpretation, and manipulation of drug concentrations. Therapeutic drug monitoring should include both serum concentration monitoring and bedside patient assessment. It is important to avoid the common pitfall of treating the drug concentration and not the patient. Several precautions should be considered when interpreting serum concentrations in the neonate: 1) verify the relationship between time of drug administration and time of plasma sampling, 2) avoid obtaining a serum concentration during the alpha or distribution phase of a drug, 3) consider whether a drug has active metabolites, 4) dene therapeutic goals, and 5) appreciate the differences between receptor drug concentration and serum drug concentration.

Half-life
Half-life (t12) is the time required for a serum concentration to decrease by 50% after absorption and elimination are complete. With rst-order kinetics, it takes the same amount of time for the serum concentration to drop from 100 to 50 mcg/mL as it does to decrease from 4 to 2 mcg/mL. Half-life is important because it determines both the amount of time to reach steady state (three to ve half-lives) and the appropriate drug dosing interval. A potential drawback to this kinetic parameter is that it is a dependent parameter. Specically, the half-life of a drug depends on both Vd and clearance. Therefore, the half-life of a drug may change simply because the Vd has changed. Drug half-life also can be calculated using the elimination rate constant. Hence, both half-life and elimination rate describe the speed with which a drug concentration decreases in the serum.

Basic Principles of Pharmacodynamics


Pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting therapeutic or toxic effect. There are three primary pharmacodynamic models: 1) Emax, 2) sigmoid Emax, and 3) linear. With Emax and sigmoid Emax, a concentration of zero no effect is measured. Plotting the drug concentration versus pharmacologic effect relationship results in a hyperbola or sigmoid curve (Fig 5). With these models, the largest changes in drug effect are seen at the lower end of the concentration scale. In clinical practice, the linear model often is used to describe the pharmacologic effect seen between 20% to 80% of Emax. With the linear model, a non-zero effect value is allowed when drug concentration is zero and may be used to describe the patients baseline. Concentration-effect curves do not always follow the same blueprint when serum drug concentrations are increasing as they do when they are decreasing. A classic example of this involves the opioids in which tolerance to a specic drug concentration may develop during therapy, with the subsequent weaning-off process resulting in very different drug-effect paired points. This effect is known as hysteresis and is seen as clockwise or counterclockwise loops for the concentration-effect plots (Fig 6).

Clearance
Clearance (Cls) is the most important pharmacokinetic parameter because it determines the steady-state concentration for a given dose (equation 7, Table 3). Clearance describes removal of drug from plasma and is expressed as volume over time. Clearance does not indicate how much drug is removed; rather, it represents the volume of plasma from which the drug is removed completely in a given time period. Drugs may be removed from the body via renal, hepatic, or biliary clearance. Drugs that are removed hepatically are classied further as owlimited or capacity-limited. If a drug relies on hepatocellular metabolism for removal, it is classied as owlimited because a change in hepatic blood ow has a proportional change on delivery of drug to the liver for metabolism and overall drug clearance. If a drug has low intrinsic or hepatic metabolism, it is classied as capacitylimited, and hepatic uptake determines clearance, which is independent of hepatic blood ow. Capacity-limited drugs may be subdivided further into binding-sensitive and binding-insensitive drugs. Drugs that are bindingsensitive (eg, clindamycin) have increased hepatic clearance if the percent protein binding is reduced, resulting in more free drug available for removal.
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Suggested Reading
Besunder JB, Reed MD, Blumer JL. Principles of drug disposition in the neonate. A critical evaluation of the pharmacokinetic-

pharmacology pharmacology & pharmacokinetics

pharmacodynamic interface. Part I. Clin Pharmacokinet. 1988; 14:189 216 Gilman JT. Therapeutic drug monitoring in the neonate and pediatric age group. Problems and clinical pharmacokinetic implications. Clin Pharmacokinet. 1990;19:110 Gow PJ, Ghabrial H, Smallwood RA, Morgan DJ, Ching MS. Neonatal hepatic drug elimination. Pharmacol Toxicol. 2001: 88:315 Morselli PL. Clinical pharmacology of the perinatal period and early infancy. Clin Pharmacokinet. 1989;17(suppl 1):13

Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clin Pharmacokinet. 1980;5:485527 Reed MD, Besunder JB. Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am. 1989;36: 10531074 Stewart CF, Hampton EW. Effect of maturation on drug disposition in pediatric patients. Clin Pharm. 1987;6:548 564 Van den Anker JN. Pharmacokinetics and renal function in preterm infants. Acta Paediatr. 1996:85:1393399

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NeoReviews Quiz
1. Enteral absorption of an orally administered drug is inefcient in preterm neonates compared with term infants. Of the following, the factor most likely to decrease enteral absorption of a drug in preterm neonates is: A. B. C. D. E. Acidity of the drug. Increased gastric acid secretion. Nonionization of the drug. Presence of enteral feeding. Rapid gastric emptying.

2. Percutaneous absorption of a topically applied drug is increased in preterm neonates compared with term infants. Such absorption, however, can cause inadvertent systemic toxicity. Of the following, the drug that has been administered most successfully via a topical gel is: A. B. C. D. E. Alcohol. Aminoglycoside. Corticosteroid. Hexachlorophene. Theophylline.

3. Protein binding has a profound effect on the therapeutic actions of a drug because only unbound or free drug is pharmacologically active. Of the following, the drug that has the highest protein binding is: A. B. C. D. E. Ampicillin. Caffeine. Digoxin. Indomethacin. Phenobarbital.

4. Drug metabolism involves uptake of the drug into the liver cell by acceptor proteins, which is followed by transformation of the drug within the liver cell by phase I and phase II enzymatic reactions. Of the following, the enzymatic reaction most likely to be present at birth, even in a preterm neonate is: A. B. C. D. E. Acetylation. Glucuronidation. Hydroxylation. Methylation. Sulfation.

5. Renal elimination of a drug involves glomerular ltration, tubular reabsorption, and tubular secretion. Drugs such as furosemide and morphine, which depend on tubular secretion for elimination, have decreased clearance in newborns whose renal function is immature. Of the following, the postnatal age at which the renal tubular secretion is most likely to mature is: A. B. C. D. E. 3 months. 6 months. 9 months. 12 months. 15 months.

6. Clinical pharmacokinetics is a mathematical description of processes in the body that alter drug concentrations, and it is used to maximize efcacy and minimize toxicity of medications that have a narrow therapeutic range. Of the following, the most accurate statement regarding the concepts of pharmacokinetics in clinical application is that: A. B. C. D. E. Clearance represents the amount of drug removed from plasma in a given time period. Half-life of a drug is important for calculating the patient-specic loading dose of the drug. Lipophilic drugs are best described by the one-compartment model of drug distribution. Plot of natural log of plasma concentration of a drug versus time is linear in rst-order elimination. Volume of distribution of a drug is useful for determining the appropriate drug dosing interval.

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