Absorption

Following oral exposure to a xenobiotic, absorption occurs primarily from the small intestine. In both neonates and adults, the surface area of the small intestine is large. Therefore the extent of drug absorption probably does not differ clinically between normal pediatric and adult animals. However, the pediatric patient has a decreased gastric emptying time and irregular intestinal peristalsis and tends to have a slower rate of absorption (Table 11-1). These factors may result in the development of lower peak plasma toxin concentrations. The decreased rate of absorption may actually protect against toxic drug concentrations.^4,5 However, in neonates before colostrum is absorbed, these protective mechanisms may not be present. Before colostrum absorption, the permeability of the intestinal mucosa is increased, which also increases the rate of toxin uptake, including the uptake of compounds that normally would not reach the systemic circulation. Intestinal permeability rapidly decreases after colostrum ingestion.^5,6 This may well be induced by endogenous release of hydrocortisone or adrenocorticotropic hormone (ACTH). Exogenous supplementation of these hormones to the mother within 24 hours prepartum prevents the increase in permeability and uptake of colostrum.

Table 11-1 Altered Xenobiotic Disposition in Pediatric Patients

Several other factors may affect small intestinal drug absorption in pediatric patients. Newborns have a neutral gastric pH, and the rate of progression to adult levels depends on the species involved.^4,6 Achlorhydria (increased gastric pH) may cause decreased absorption of many compounds that require disintegration and dissolution or that need to be ionized in a less acidic environment (e.g., weak acids). Milk diets can interfere with absorption of toxic compounds by reducing gastric motility or interacting directly with the toxins. The “unstirred water layer” adjacent to the surface area of the mucosal cells is thicker in the neonate compared with the older pediatric patient, and this may limit the rate of absorption of some compounds. Absorption of fat-soluble compounds increases as biliary function develops. Both extrahepatic metabolism and enterohepatic circulation may be altered as microbial colonization of the gastrointestinal tract occurs.^7,8 Absorption from the rectal mucosa is rapid in neonates.

Absorption of xenobiotics administered parenterally to pediatric animals varies from that in adults. As muscle mass develops, with its accompanying increase in blood flow and maturation of the vasomotor response, the rate of absorption following intramuscular administration of xenobiotics is altered.⁷ Subcutaneous administration of potentially toxic drugs may exhibit variable absorption rates relative to the patient’s age. Smaller amounts of body fat, but greater water volume, may result in quicker absorption of toxins compared with that in adults.⁹

It is suspected that environmental temperature influences subcutaneous absorption. This is especially true in neonates whose thermoregulatory mechanisms are poorly functional. If the neonate is in a cold environment, subcutaneous xenobiotic absorption tends to be reduced. The same thing would be expected for a patient that presents in a hypothermic state. Intraperitoneal exposure to xenobiotics may exhibit rapid absorption in the pediatric patient.

Percutaneous absorption of xenobiotics may be greater in pediatric patients. Percutaneous absorption is directly related to skin hydration, which is highest in neonates. Topical exposure to potentially toxic lipid-soluble compounds (e.g., hexachlorophene and organophosphates) places the pediatric patient at higher risk of significant absorption.

Volatile gases are absorbed rapidly from the pediatric respiratory tract because of greater minute ventilation.¹ Young animals are more sensitive to the effects of inhaled gases.

Distribution

The two major differences between adult and pediatric patients relative to xenobiotic distribution are those of body fluid compartments and xenobiotic binding to serum proteins. Body fluid compartments undergo tremendous alterations as the neonate grows. As the neonate matures, significant changes occur in both the percentage of total body water and the ratio of compartmental volumes. Although both the percentage of total body water and the volume of the extracellular versus the intracellular compartment decrease as the animal ages, the change in the ratio of extracellular to intracellular volume is significantly greater.¹⁰ Daily fluid requirements are greater in neonatal and pediatric patients because a larger proportion of their body weight is represented by body water. The net effect on xenobiotic distribution depends on these differences in body compartments. Most water-soluble compounds are distributed into extracellular fluids. Plasma concentrations of these compounds are lower in pediatric patients compared with adults because the volume into which the compound is distributed is greater in the young. Unbound lipid-soluble compounds have the same type of distribution because they are distributed into total body water. Changes in xenobiotic distribution directly alter the half-life of that xenobiotic. Increases in distribution directly decrease the plasma concentration, a fact that may potentially protect the pediatric patient from toxic xenobiotic concentrations.¹¹

Distribution of lipid-soluble compounds that accumulate in the fat (e.g., some organophosphates and chlorinated hydrocarbons) may be decreased because of a smaller proportion of body fat in the pediatric patient. Xenobiotic plasma concentrations may be higher, but the half-life is shorter. The movement of many fat-soluble compounds may be facilitated by their high tendency to bind to plasma proteins. This binding decreases their ability to be distributed to target tissues.

Predicting the distribution of highly protein bound compounds is complicated in the pediatric patient. Most compounds are bound to serum albumin, and basic xenobiotics have a high affinity for α₁-glycoproteins. Both of these proteins are available in lower concentrations in pediatric patients.¹² Additionally, differences in albumin structure and competition with endogenous substrates (e.g., bilirubin) for binding sites may decrease protein binding.^5,13 If bound xenobiotics are displaced, the risk of toxicity increases as the concentration of free pharmacologically active compounds rises. When a compound has a narrow therapeutic index and is highly protein bound, these age-related changes are significant. Xenobiotic half-life may rise because of increased amounts of compound that are unbound, allowing free distribution to the tissues and decreasing the plasma xenobiotic level.¹³ Despite the increased volume of distribution, the half-life of a compound may be “normalized” by the increased clearance of free xenobiotic.

Pediatric patients also have differences in regional organ blood flow that may alter xenobiotic disposition. Significant differences in renal blood flow can result in alterations in xenobiotic excretion.^14,15 Proportionally greater blood flow to the heart and brain in pediatric patients¹ increases the risk of adverse effects that may result from lower exposures to cardiac and central nervous system toxins. Neonatal patients have an increased permeability of the blood-brain barrier. This protects the brain from deficiencies in nutritional fuels in stressful states because oxidizable substrates, such as lactate, can pass from the blood into the central nervous system.¹⁶ However, this mechanism also increases the potential for central nervous system exposure to toxins. Brain cells that are normally protected in adults are at higher risk of exposure to toxins in the neonate.