Pharmacokinetic Variation

Pharmacokinetics describes the time course of mechanisms that determine the level of drug (and its metabolites) in tissues and at receptor sites and terminate its biological actions (see pp. 18-50). Mathematical expressions that relate drug concentration to standard pharmacokinetic parameters (such as drug dose, dosing interval, bioavailability, rate of elimination, apparent volume of distribution, plasma half-life, and drug clearance) lend quantitative precision to estimates of the relative effects of absorption, distribution, and elimination on the response.

At the beginning of life, pharmacokinetic variations are related to matura-tional increases in liver and kidney function and to variations in gastrointestinal absorption, tissue distribution, plasma protein binding, and ''drug extraction ratio'' characteristics, but other physiological processes contribute to these variations.

Drug Absorption

In healthy infants and children, most of the physiological changes important for gastrointestinal absorption of drugs that are usually orally administered are quite variable and undergo continuous maturational changes. Gastrointestinal transit time, the area available for absorption from different segments of the gut, and the permeability and vascularity of different segments are some of the specific variables of concern during development. The gastric emptying time in the newborn is slower than at any other time in life. Many newborn infants require 8 hours for complete gastric emptying, and in some instances it may be much longer. In general, movements during the neonatal period are irregular and unpredictable, and are subject to various influences including nutritional status, diet, and feeding pattern. Changes in gastric acidity are cyclic, showing initially a low acidity that rises abruptly to adult levels on the first day of birth, and then declines to an achlorhydric state by about the tenth day after birth. Thereafter the acidity gradually rises again until it attains adult levels at approximately 3 years; later in life it may decline slowly. The relative achlorhydria may partially explain the higher bioavailability of acid-labile drugs such as several penicillins, and the reduced absorption of weakly acidic drugs such as phenobarbital, phenytoin, and naldixic acid. From the studies that have examined the absorption of drugs and nutrient molecules, both passive and active enteral absorptive transport processes are judged to be fully mature by approximately 4 months after birth. Additional developmental changes such as differences in intestinal drug-metabolizing enzymes and transporter mechanisms can also alter the bioavailability, but for the most part these are incompletely characterized.7,17

In elderly persons, a preponderance of information indicates that intestinal absorption of most drugs that cross the gastrointestinal barrier by diffusion, the primary process for absorption of orally administered drugs, is not altered to an extent that is clinically relevant. For drugs that cross the intestinal barrier by carrier-mediated transporter mechanisms, such as calcium, iron, vitamins, and possibly nucleoside drugs, absorption may occur at lower rates, although the data are limited. Because of a reduction in tissue blood perfusion associated with atrophy of the epidermis and dermis that occurs with advancing age, transdermal drug absorption may be diminished in the elderly. For the same reason, drug absorption from subcutaneous and muscular tissue sites may also occur at lower rates.8,9,18

Drug Distribution

Total body water, extracellular water, and intracellular water are functional compartments of pharmacological interest because the distribution of different classes of drugs within the body often corresponds to one of these spaces. The size of these body water compartments and the changes from birth to adulthood originally described by Friis-Hansen19 have been reviewed in the present context by several authors.7-9,20 Total body water is approximately 78% of body weight at birth, and decreases sharply to 60% at 1 year, which closely approximates that at maturity (Table 4.1 and Figure 4.1B). The extracellular water space is much greater in comparison to body weight in the newborn infant (45%) than in a 1-year-old child (27%), and subsequently decreases until it attains the adult standard at approximately 3 years (17%). This change is almost entirely due to changes in interstitial volume, because the size of the plasma water compartment, a component of extracellular water, is unaltered (4-5%) throughout life. The change in intracellular water space initially opposes that of total body and extracellular water, increasing from 34% of body weight at birth to 43% at 3 months and then decreasing to a value quite close to that at birth (40%). After 3 years of age, the size of all three compartments reaches their adult values. Person-to-person variations, especially at birth, are large but do not overlap those of older children or adults.

Differences in drug distribution can also be due to differences in the amount of binding protein, in the strength of protein-drug interaction, or a combination of these factors.7 Levels of serum proteins have been studied at various ages from gestation through middle age into senescence. Albumin, the major drug-binding component of plasma, is present in fetal serum by 4 weeks of gestational age, increasing in proportion to gestational age and reaching an average of 1.8 g/100 ml of serum by 26-27 weeks gestation and 2.5 g /100 ml serum by 30-31 weeks gestation. Plasma albumin levels are sufficiently characteristic of fetal maturity that they can be used clinically to assess the gestational age of the newborn, and levels of less than 2.5 g/100 ml of serum, for example, are taken as evidence of immaturity. Levels do not appear to fluctuate appreciably during childhood, and in the adult they decline slowly with age. An average decrease of 20% occurs between the young adult and an elderly person of 60-70 years in one report,

Table 4.1 Variation in Body Water Compartments with


Table 4.1 Variation in Body Water Compartments with


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