Neonates renal drug excretion

It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional capacity may be diminished in the elderly. Thus, compounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug secretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups. 

Age-related alteration of renal function is a very important factor in selecting the dose regimen. Renal function in newborns is incompletely developed. Neonatal renal plasma flow and glomerular filtration rates (normalized for body surface) are only 30-40% of those of adults. The half-life of penicillin G is 3.2 h in newborns (up to 6 days of age) and 1.4 h in infants (14 days of age or older), whereas in older children and adults, it is about 0.5 h. The mean half-life of gentamicin is about 5h in newborns under 1 week of age and about 3 h in infants 1-4 weeks of age. The half-life of gentamicin in older infants and adults is approximately 2 h. Thus, drugs that depend on renal excretion as the principal mode of elimination would be expected to have a longer residence time in infants. 

RENAL EXCRETION Excretion of drugs and metabolites in the urine involves three distinct processes glomerular filtration, active tubular secretion, and passive tubular reabsorption. Changes in overall renal function generally affect aU three processes to a similar extent. In neonates, renal function is low compared with body mass but matures rapidly within the first few months after birth. During adulthood, there is a slow decline in renal function, 1% per year, so that in elderly patients a substantial degree of functional impairment may be present. 

The renal excretion of drugs depends on glomerular filtration, tubular secretion, and tubular absorption. A twofold increase in glomerular filtration occurs in the first 14 days of life [36], The glomerular filtration rate continues to increase rapidly in the neonatal period and reaches a rate of about 86 mL/min per 1.73 m2 by 3 months of age. Children 3-13 years of age have an average clearance of 134 mL/min per 1.73 m2 [37]. Tubular secretion approaches adult values between 2 and 6 months [11], There is more variability observed in maturation of tubular reabsorption capacity. This is likely linked to fluctuations in urinary pH in the neonatal period [38],... 

Chloramphenicol is inactivated in the liver by glu-curonosyltransferase and is rapidly excreted (80-90% of dose) in the urine. About 5 to 10% of the administered drug is excreted unchanged. Renal elimination is by tubular secretion and glomerular filtration. Other degradation pathways are known to exist and may account for some of the toxicity seen in neonates and children. 

John EG Guignard JP. Development of renal excretion of drugs during ontogeny. In Neonatal and fetal medicine. Polin RA FowWW Eds. Saunders WB, Philadelphia, pp 188-193,1997. 

Metabolism in pediatric patients can be quite different from adults. In the very young infant, drug uptake by the liver is decreased due to reduced transport proteins. The biliary excretion of antibiotics with dual routes of elimination suggests that hepatic transport maturation is even slower than glomerular filtration or renal transport maturation. Overall, mixed function oxidases are present at 30-50% of adult activity, while individual enzymes may be less than 5% of adult activity. In particular, isoenzymes of CYP 2C9 and 1A2 have greatly reduced activity in neonates however, there is a rapid increase in 2C9 activity in the first weeks of life. After birth. Phase I and II enzymes have a programmed order of expression, which is different for each isoenzyme. Some isoenzymes increase in days, others over weeks, and stUI others over months. 

NAG, along with other urinary enzymes, has been used to evaluate drug induced tubular damage as in the case of acetaminophen [113], 5-aminosalicyate/ sulfasalazine in patients being treated for inflammatory bowel disease [114], and the relative nephrotoxicity of differing aminoglycoside dose schedules in neonates [115]. Assess of the urinary excretion of NAG have also been reported in hypertensive patients [116] and in patients with chronic renal failure due to various causes [117]. However, to date, it is considered to be an ancillary but non-definitive marker of renal disease. 

Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. About 50% of chloramphenicol is bound to plasma proteins this is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dose adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. Drug administration after hemodialysis minimizes this effect. Variabihty in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug levels. 

Two mechanisms contribute to chloramphenicol toxicity in neonates (1) a developmental deficiency of glucuronyl transferase, the hepatic enzyme that metabolizes chloramphenicol and (2) inadequate renal excretion of unconjugated drug. At the onset, plasma chloramphenicol concentrations usually exceed 100 pg/mL but may be only 75 pg/mL. For children under 2 weeks of age, the maximum daily chloramphenicol dose is 25 mg/kg of body weight thereafter, fuU-term infants may receive up to 50 mg/kg daily. 

Developmental changes in renal function, particularly glomerular filtration and active tubular secretion, affect the renal excretion of many drugs. In the preterm neonate the kidney is still undergoing development or nephrogenesis. Renal function at birth, and how it develops after birth, are related to the maturity of the developing nephrons. 

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