252 Disposition of Chloramphenicol in Newborn Infants

Glazer, John L; Danish, Michele; Yachetti, Stephen D; Warren, W. Stuart; Yaffe, Summer J.

doi:10.1203/00006450-197804001-00257

Cited by 5 publications

(3 citation statements)

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“…However, clearly nothing in our current understanding of K m and V max can explain how the pharmacological and clinical factors we identified as predictors could affect both enzyme affinity and maximum velocity for isoniazid acetylation. However, the historical disaster of gray baby syndrome in children treated with the drug chloramphenicol suggests that maturation has a major effect on enzyme function ( Glazer et al, 1980 , Mulhall et al, 1983 , Sutherland, 1959 ). The functional deficiency in the UDP-glucuronyl transferase enzyme system encountered in the first few weeks of life, especially in premature neonates, led to cardiovascular collapse when high concentrations of the antibiotic were achieved in the children ( Glazer et al, 1980 , Mulhall et al, 1983 , Sutherland, 1959 ).…”

Section: Discussionmentioning

confidence: 99%

The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

Rogers¹,

Hiruy

Pasipanodya

et al. 2016

EBioMedicine

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N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax) and affinity (Km) in children 0–10 years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥ 5.3 years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm.

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Section: Discussionmentioning

confidence: 99%

The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

Rogers¹,

Hiruy

Pasipanodya

et al. 2016

EBioMedicine

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“…In 2 studies, the investigators reported unusual serum concentrations of chloramphenicol in certain infants and children (Friedman et al 1979;Glazer et al 1980). In 2 studies, the investigators reported unusual serum concentrations of chloramphenicol in certain infants and children (Friedman et al 1979;Glazer et al 1980).…”

Section: Discussionmentioning

confidence: 99%

Intravenous Infusion Conditions

Nahata

1993

Clinical Pharmacokinetics

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Drugs are often given intravenously with an expectation that the predicted serum concentrations will be achieved rapidly. Routine pharmacokinetic monitoring of some drugs may be of limited value, unless the effect of intravenous drug delivery systems on serum concentrations is known. In vitro studies have demonstrated that the actual time for complete drug delivery can be markedly longer than predicted and is dependent inter alia on factors including the delivery device, flow rate, injection site, drug volume and tubing diameter. Studies in paediatric patients have shown that the serum concentrations of drugs, including aminoglycosides and chloramphenicol, are strongly influenced by intravenous drug delivery systems. Similarly, data from adult patients have indicated that a drug delivery system can affect serum concentrations of aminoglycosides. Some data are available about the pharmacokinetics of drugs delivered by newer devices, e.g. controlled release infusion systems, membrane devices and implanted pumps, but additional research is needed to determine their predictability of delivery and pharmacokinetics of commonly used drugs. To achieve optimal therapeutic outcomes in patients, it is crucial to understand the impact of an intravenous drug delivery system on serum concentrations and to develop guidelines for pharmacokinetic monitoring.

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“…However, it is biologically inactive and must be hydrolyzed following administration to release the antimicrobially active compound. Moreover, the serum disappearance rate of chloramphenicol succinate (CP-S) in infants and children was found to be highly variable and unpredictable with the inactive ester persisting in the serum [3][4][5]. Thus, the rate of hydrolysis may play an important role in its efficacy and toxicity.…”

Section: Introductionmentioning

confidence: 99%

Developmental Changes in Hepatic Esterase Activity towards Chloramphenicol Succinate and Its Michaelis-Menten Constant of Liver, Kidney and Lung in Human

Yamakawa¹,

Itoh²,

Onishi³

et al. 1984

Dev Pharmacol Ther

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The hepatic esterase activities towards chloramphenicol succinate were determined in the tissues from 45 human subjects, including 18 electively aborted fetuses, 5 premature and 8 full-term newborn babies, 8 infants and 6 adults. The enzyme activities in the tissues from the fetuses and neonates were significantly lower compared with those obtained from the infants and adults. This suggests that the activity showed postnatal development. Kinetic studies of the esterase activity revealed that hepatic K(m) values were similar to those of the lung, but renal K(m) values were about 3 times higher than those of the liver and lung. In each organ, no age-related changes in K(m) values were observed. However. all the V(max) values in each organ showed developmental increases. Therefore, the liver plays the most important role in hydrolysis of chloramphenicol succinate when the weight of the organ is taken into consideration.

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252 Disposition of Chloramphenicol in Newborn Infants

Cited by 5 publications

References 0 publications

The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

Intravenous Infusion Conditions

Developmental Changes in Hepatic Esterase Activity towards Chloramphenicol Succinate and Its Michaelis-Menten Constant of Liver, Kidney and Lung in Human

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