The maturation of organ systems during fetal life and childhood exerts a profound effect on drug disposition. The maturation of drug-metabolising enzymes is probably the predominant factor accounting for age-associated changes in non-renal drug clearance. The group of drug-metabolising enzymes most studied are the cytochrome P450 (CYP) superfamily. The CYP3A subfamily is the most abundant group of CYP enzymes in the liver and consists of at least 3 isoforms: CYP3A4, 3A5 and 3A7. Many drugs are mainly metabolised by the CYP3A subfamily. Therefore, maturational changes in CYP3A ontogeny may impact on the clinical pharmacokinetics of these drugs. CYP3A4 is the most abundantly expressed CYP and accounts for approximately 30 to 40% of the total CYP content in human adult liver and small intestine. CYP3A5 is 83% homologous to CYP3A4, is expressed at a much lower level than CYP3A4 in the liver, but is the main CYP3A isoform in the kidney. CYP3A7 is the major CYP isoform detected in human embryonic, fetal and newborn liver, but is also detected in adult liver, although at a much lower level than CYP3A4. Substrate specificity for the individual isoforms has not been fully elucidated. Because of large interindividual differences in CYP3A4 and 3A5 expression and activity, genetic polymorphisms have been suggested. However, although some gene mutations have been identified, the impact of these mutations on the pharmacokinetics of CYP3A substrates has to be established. Ontogeny of CYP3A activity has been studied in vitro and in vivo. CYP3A7 activity is high during embryonic and fetal life and decreases rapidly during the first week of life. Conversely, CYP3A4 is very low before birth but increases rapidly thereafter, reaching 50% of adult levels between 6 and 12 months of age. During infancy, CYP3A4 activity appears to be slightly higher than that of adults. Large interindividual variations in CYP3A5 expression and activity were observed during all stages of development, but no apparent developmental pattern of CYP3A5 activity has been identified to date. Profound changes occur in the activity of CYP3A isoforms during all stages of development. These changes have, in many instances, proven to be of clinical significance when treatment involves drugs that are substrates, inhibitors or inducers of CYP3A. Investigators and clinicians should consider the impact of ontogeny on CYP3A in both pharmacokinetic study design and data interpretation, as well as when prescribing drugs to children.

Cytochrome P450 3A: ontogeny and drug disposition.

Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed ‘complete’. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an ‘exceeding’ transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

Placental Transfer of Drugs Administered to the Mother

Maturation of drug systemic clearance mechanisms during the postnatal period produces dramatic and rapid changes in an infant's capacity to eliminate drugs. A tentative general mathematical model describing the ontogeny of hepatic cytochrome P450 (CYP) enzyme-mediated clearance and renal clearance due to glomerular filtration in the first 6 months of life was elaborated from age-specific in vitro hepatic microsomal activity data (normalised to amount of hepatic microsomal protein) for enzyme-specific probe substrates and in vivo probe substrate data for glomerular filtration (normalised to bodyweight), respectively. The model predicts an age- and clearance pathway-specific Infant Scaling Factor (ISF) for the first 6 months of life. The ISF reflects functional maturation of a specific clearance pathway (normalised to bodyweight) relative to adult values. Therefore, the ISF directly correlates adult clearance values with an infant's capacity to eliminate drugs. Substitution of appropriate model parameter estimates and the age of the infant into the model provides an estimated ISF value, which may then be used to predict the contribution of a particular clearance pathway to total systemic clearance in the infant when adult systemic clearance values are known. The model was tested for its ability to predict infant systemic clearance of drugs whose elimination is principally mediated by a single CYP enzyme or by glomerular filtration. The model performed reasonably well for CYP1A2 and CYP3A4, but poorer predictions were obtained for CYP2D6 and CYP2C because of lack of model complexity and/or inadequate hepatic microsomal activity data to fully describe the maturational process of functional enzyme. For renal clearance due to glomerular filtration, data normalised to bodyweight (kg) showed a limited maturational trend, suggesting that adult renal clearances normalised to bodyweight might reasonably predict infant renal clearances in the first 6 months of life. The model provided reasonable predictions of renal clearance due to glomerular filtration in the infant.

Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants Part I

OBJECTIVE: Despite the widespread use of benzodiazepines during pregnancy and lactation, little information is available about their effect on the developing fetus and on nursing infants. The authors review what is currently known about the effects of benzodiazepine therapy on the fetus and on nursing infants. METHODS: A MEDLINE search of the literature between 1966 and 2000 was conducted with the terms "benzodiazepines," "diazepam," "chlordiazepoxide," "clonazepam," "lorazepam," "alprazolam," "pregnancy," "lactation," "fetus," and "neonates." RESULTS: Currently available information is insufficient to determine whether the potential benefits of benzodiazepines to the mother outweigh the risks to the fetus. The therapeutic value of a given drug must be weighed against theoretical adverse effects on the fetus before and after birth. The available literature suggests that it is safe to take diazepam during pregnancy but not during lactation because it can cause lethargy, sedation, and weight loss in infants...

/pdf/effects-of-commonly-used-benzodiazepines-on-the-fetus-the-1aedljtldj.pdf

Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant.

The effects of benzodiazepine use during pregnancy and lactation

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

Placental transfer of diazepam and its disposition in the newborn

Induction of drug metabolizing enzyme activities in the human fetus and in the newborn infant

The problem of induction of microsomal enzyme activities in the human fetus and in the neonate was studied by measuring diazepam metabolites in the urine of five subjects pretreated with phenobarbital, either during fetal life or after birth A very considerable increase of urinary excretion of hydroxylated and conjugated compounds was observed These findings may be considered as an indirect evidence of induction of drug metabolizing enzyme activities during the last part of gestation and shortly after birth Present knowledge on liver enzyme induction in fetuses and neonates are critically reviewed

/pdf/induction-of-drug-metabolizing-enzyme-activities-in-the-2f2q7gjlwl.pdf

Induction of drug metabolizing enzyme activities in the human foetus and in the newborn infant

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Placental transfer of diazepam and its disposition in the newborn

Induction of drug metabolizing enzyme activities in the human fetus and in the newborn infant

Placental transfer of diazepam and its disposition in the newborn

Induction of drug metabolizing enzyme activities in the human foetus and in the newborn infant