Monitoring of aminoglycoside serum concentrations.
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Adolescent↗
Biomedical subjects
G L Kearns
Publications and source records attributed to G L Kearns.
Lipid amphotericin preparations.
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Amphotericin B↗
Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.
BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.
Administration, Oral↗
Single dose pharmacokinetics of linezolid in infants and children.
BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.
Acetamides↗
Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin.
The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.
Adolescent↗
Acetaminophen intoxication during treatment: what you don't know can hurt you.
For over two decades, pediatricians have been made aware of the potential risk associated with the acute ingestion of large single and/or multiple doses of acetaminophen (APAP). Clearly, APAP-induced hepatotoxicity remains as a recognized medical emergency which, when treated promptly with appropriate gastrointestinal decontamination and when indicated, with the antidote N-acetylcysteine, has a uniformly good clinical outcome. Recently, the hepatotoxic potential associated with "therapeutic" APAP administration has been brought to the attention of the pediatric community. This review explores the issue of APAP toxicity with therapeutic intent by examining both the clinical literature and also, relevant information concerning the basic pharmacology and toxicology of this old and widely used nonprescription drug. A "risk profile" is developed with regard to factors that may predispose infants and children to this iatrogenic form of toxicity so that the awareness of physicians and other caregivers (including parents) can be heightened and preventative education administered. As is true for most all potentially beneficial medicines used in pediatrics, awareness of the actual amount of drug received from all sources and caution to not exceed the age-appropriate dosing guidelines (i.e., both amount and duration) contained in the approved labeling for all products containing APAP will insure safe and effective therapy.
Acetaminophen↗
Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets.
Cefpodoxime is an oral third-generation cephalosporin used for the treatment of acute upper-respiratory tract infections caused by susceptible bacteria in children. Although not indicated for the treatment of bacterial meningitis, it is used to treat other infections produced by organisms associated with meningitis and may obscure the result of cerebrospinal fluid (CSF) cultures in children who develop meningitis while receiving oral antibiotics if sufficient concentrations are achieved in the CSF. This study evaluated the disposition of cefpodoxime and penetration into CSF in piglets. Fifteen Landacre-Camborough cross piglets (10-20 days old) received cefpodoxime proxetil oral suspension (10 mg/kg). Repeated plasma and CSF samples were collected over 24 hours for quantitation of cefpodoxime by HPLC. Pharmacokinetic analysis was performed on both plasma and CSF data. The plasma concentration versus time data for cefpodoxime were best characterized using a one-compartment model with first-order absorption. The mean (+/- SD) pharmacokinetic parameters for Cmax, tmax, and AUC0-infinity were 23.3 +/- 12.9 mg/L, 3.9 +/- 1.4 h, and 237 +/- 129 mg/L.h, respectively. CSF/plasma ratios for AUC0-infinity demonstrated a mean cefpodoxime penetration of approximately 5%. CSF penetration of cefpodoxime was evident following a single oral dose of cefpodoxime proxetil suspension. Despite the small percentage of total cefpodoxime dose distributing into the CSF, the resultant concentrations approached or exceeded the MIC90 for many bacterial pathogens considered susceptible to cefpodoxime. Accordingly, clinicians should use caution in the interpretation of CSF cultures in patients who develop clinical signs and symptoms consistent with meningitis and who have been previously treated with cefpodoxime.
Animals↗
Impact of plasmapheresis on disopyramide elimination.
The impact of plasmapheresis on the disposition of disopyramide was investigated in a 16-year-old female with systemic lupus erythematosus. Determination of total disopyramide plasma concentrations immediately prior to and following a 4-h plasmapheresis treatment revealed a significant reduction (i.e., 1.77 to 0.7 mg/l or approximately 60%). However, reassessment of the total serum concentration after 1.5 h (i.e., post equilibrium) revealed a rebounding of the value to 1.64 mg/l. Associated with this reduction in total serum levels was a decrease in the protein-bound fraction of disopyramide from 69.5% (pre treatment) to 48.6% (post treatment) that corresponded to a commensurate reduction in the concentration of alpha1-acid glycoprotein (i.e., 119 mg/dl pre treatment to 48.9 mg/dl post treatment). Despite these alterations in disopyramide concentrations, the procedure removed only 2.7% of the disopyramide dose and was not associated with the appearance of a cardiac dysrhythmia.
Adolescent↗
Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.
Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that show superiority of any particular dose are lacking. We compared metabolic ratios from six different dextromethorphan phenotyping doses to ascertain whether linearity existed over a dosage range. Forty subjects were enrolled in the study. Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and 1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6 activity. Single blood samples were obtained for CYP2D6 genotyping, which revealed one poor metabolizer and 39 extensive metabolizers. A statistical difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg dose compared with the other four doses. None of the 39 genotypic extensive metabolizers were incorrectly phenotyped with any of these doses. These data support the use of moderate doses of dextromethorphan for phenotyping to avoid dose dependency.
Adult↗
Developmental pharmacodynamics of cyclosporine.
OBJECTIVE: To determine the relationship between human development and in vitro cyclosporine (INN, ciclosporin) pharmacodynamics. METHODS: Fifty-six subjects ranging in age from 3 months to 39 years were studied in this prospective laboratory investigation at a university children's hospital and clinical pharmacology laboratory. Peripheral blood monocytes were separated from whole blood and cultured with phytohemagglutinin A (5 microg/mL) and cyclosporine (0, 6.25, 12.5, 25, 50, 100, 500, 1000, 2500, and 5000 ng/mL). Peripheral blood monocytes cultures were assayed for cell proliferation and supernatant interleukin-2 concentration with use of radionuclide DNA tagging and enzyme-linked immosorbent assay, respectively. After concentration-effect modeling, summary pharmacodynamic parameters, including the maximal drug effect (Emax) and cyclosporine concentration at which 50% of maximal effect (IC50) and 90% of maximal effect (IC90), were determined. These parameters were compared between four consecutive subject age groups: infants (0-1 years), children (>1-4 years), preadolescents (>4-12 years), and adults (>12 years). RESULTS: The peripheral blood monocytes of the infants showed a twofold lower mean IC50 (peripheral blood monocyte proliferation) and sevenfold lower mean IC90 (interleukin-2 expression) than peripheral blood monocytes from older subjects. The three older age groups were similar with respect to mean IC50 and Emax (peripheral blood monocyte proliferation). Lymphocyte subtype proportions measured in peripheral blood monocytes preparations from each age group were generally similar. The experimental conditions (eg, general anesthesia and cyclosporine solvents) did not affect peripheral blood monocytes proliferation, but the highest experimental cyclosporine concentration (ie, 5000 ng/mL) was associated with decreased peripheral blood monocytes viability. CONCLUSIONS: Cyclosporine pharmacodynamics in vitro are related to age. This factor, if neglected, may be a source of iatrogenic risk during pediatric immunosuppressive therapy.
Adolescent↗
Investigation of terbinafine as a CYP2D6 inhibitor in vivo.
BACKGROUND: Terbinafine is an orally active antifungal used in the treatment of dermatophytoses. To date, studies evaluating the effect of terbinafine on the cytochromes P450 have failed to show any significant interactions. This prospective open-label study was designed to confirm our previous finding that terbinafine may inhibit CYP2D6. METHODS: Nine healthy volunteers were enrolled in this study-6 genotypically consistent with an extensive metabolizer phenotype and 3 genotypic poor metabolizers for CYP2D6. The change in CYP2D6 enzyme activity before (x 3) and after (monthly x 6 months) administration of terbinafine (250 mg once daily x 14 days) was evaluated with the dextromethorphan to dextrorphan urinary metabolite ratios. On each study day a predose urine sample was collected, 0.3 mg/kg dextromethorphan was administered, and urine was collected for 24 hours. Dextromethorphan and its metabolites were quantified from urine by HPLC. RESULTS: Baseline phenotype values were concordant with individual genotype. In all extensive metabolizers, the administration of terbinafine resulted in a dramatic increase in the dextromethorphan/dextrorphan ratio, converting 4 of the 6 extensive metabolizers into phenotypic poor metabolizers. On average, a 97-fold increase in ratio (range, 35 to 265) was observed for extensive metabolizers after the administration of terbinafine. No significant change was observed in the metabolite ratios of poor metabolizers during the course of the study. CONCLUSIONS: Terbinafine inhibits CYP2D6 sufficiently to produce a discordance between genotype and phenotype for the enzyme. The dextromethorphan/dextrorphan metabolite ratios increased in all individuals, with otherwise functional CYP2D6 activity. The disposition of CYP2D6 substrates coadministered with terbinafine may be significantly altered in extensive metabolizers for this cytochrome P450 isoform, who comprise approximately 93% of the population.
Adult↗
Rifapentine pharmacokinetics in adolescents.
OBJECTIVE: Determination of rifapentine pharmacokinetics in healthy adolescent children. DESIGN: Prospective Phase II clinical trial. SETTING: Clinical research center within a university children's hospital. PATIENTS: Twelve subjects ranging in age from 12 to 15 years, male and female. INTERVENTIONS: A single oral dose of rifapentine was administered to healthy adolescent volunteers, 450 mg if <45 kg or 600 mg if > or =45 kg. Blood was collected at serial intervals (0, 2, 3, 4, 5, 6, 8, 12, 18, 24, 48 and 72 h postdose). Subjects were observed for adverse effects during the period of study. MEASUREMENTS: High pressure liquid chromatography was used to measure the plasma concentration of rifapentine and 25-desacetyl rifapentine in each blood sample. For each subject a plot of mean plasma concentration vs. time data for rifapentine and its metabolite (i.e. 25-desacetyl rifapentine) were created. Subsequently model-independent methods were used to determine the pharmacokinetic profiles for each subject. RESULTS: All subjects tolerated rifapentine without adverse effects. The 2-h postdose plasma concentrations of rifapentine (6.59 to 9.05 microg/ml) and 25-desacetyl rifapentine (0.57 to 2.64 microg/ml) far exceeded the MIC of Mycobacterium tuberculosis to rifapentine (approximately 0.12 microg/ml). The combination of a high Cmax (rifapentine, 9.95 to 18.63 microg/ml; 25-desacetyl rifapentine, 3.73 to 7.46 microg/ml) and lengthy terminal elimination phase t1/2 (rifapentine, 10 to 23 h; 25-desacetyl rifapentine, 14 to 35 h) resulted in potentially effective plasma concentrations of both compounds that persisted for at least 48 h in most subjects. CONCLUSIONS: A well-tolerated oral rifapentine dose produced rapid and sustained plasma drug concentrations in adolescents that should effectively treat infections caused by M. tuberculosis. Rifapentine pharmacokinetics appears to be similar in adolescent and adult populations.
Adolescent↗
An update on the oxazolidinone antibiotics.
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Acetamides↗
Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data.
Cytochrome P4502D6 (CYP2D6) is a highly polymorphic gene locus with > 50 variant alleles which lead to a wide range in enzymatic activity. So called poor metabolizers are carriers of any two non-functional alleles of the CYP2D6 gene. CYP2D6 genotyping is cumbersome and the question of how much genotyping is necessary for an accurate phenotype prediction is still debated. The goal of this study was to determine the optimum amount of genotyping required to accurately predict the phenotype at a reasonable cost in a white North American population. To address this issue, we designed a polymerase chain reaction (PCR)/restriction fragment length polymorphism-based genotyping strategy to detect 'key' mutations linked to extensive metabolizer or poor metabolizer associated alleles in combination with extra-long PCR (XL-PCR). All mutations with the exception of gene deletions and duplications are detectable by simple restriction digestion analysis and agarose gel electrophoresis. In addition, we utilized a genotyping algorithm based on our own and published allele frequency data and phenotype analysis to calculate the probability of a correct genotype (and thus, phenotype) assignment. As little as one XL-PCR reaction followed by a maximum of six reamplification reactions allows an accurate prediction of an individual's genotype to 99.15%. As few as four reamplification reactions identify 97.9% of poor metabolizer individuals. We evaluated our model in 208 white North Americans by testing for the presence of 'key' mutations linked to CYP2D6*2, *3, *4, *6, *7, *8, *9, *10, *11, *12, *15, *17 and *18 alleles and the *5, *13 and *16 gene deletions. For all individuals, the correct phenotype has been predicted. Discordant phenotype assignment occurred in only two individuals which subsequently was attributed to CYP2D6 inhibition by concomitant drug therapy.
Algorithms↗
Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Pediatric Pharmacology Research Unit Network.
Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means +/- standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 +/- 622.1 ng/ml. The time to Cmax was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absorption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constant was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clearance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit > 90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.
Administration, Oral↗
Single oral dose escalation pharmacokinetics of pleconaril (VP 63843) capsules in adults.
Pleconaril is an orally active broad-spectrum antipicornaviral agent with excellent penetration into the central nervous system and nasal epithelium. The authors report the results of a randomized, placebo-controlled, dose escalation study of pleconaril oral capsules following single-dose administration of 50 to 1000 mg. Fifty-six healthy adults (ages 19-55) participated in the study. Each subject received a single dose of pleconaril oral capsule(s) or an identically matched placebo. Blood samples (n = 19) were obtained over 36 hours postdose, and pleconaril was quantified from plasma by gas chromatography. Pleconaril disposition was best characterized using a two-compartment open-model with first-order absorption. Fifty-five subjects completed the study (31 +/- 10 years, 77.6 +/- 11 kg). The administration of pleconaril was well tolerated. There was no difference in tmax, lambda z, ka, t1/2elim, Cl/F, or Vdss/F among the various dose groups. A significant difference in both Cmax and AUC was observed between study groups; however, this difference became insignificant when the parameters were corrected for dose. Cmax and AUC were dose proportional between 50 and 1000 mg (r2 > 0.97 and 0.90, respectively). Pleconaril demonstrates a favorable safety and pharmacokinetic profile following single-dose administration.
Administration, Oral↗
Glucuronidation in humans. Pharmacogenetic and developmental aspects.
During human development impressive changes in drug disposition occur. An important determinant of drug clearance is metabolism, something that is not only determined by ontogenic regulation but also by genetic processes which add to the variability of drug metabolism during different stages of childhood. Therefore, an understanding of the developmental regulation of different metabolic pathways, together with information on the genetic determinants of drug metabolism, will increase the knowledge of inter- and intraindividual variability in drug disposition during childhood. Conjugation has historically received less attention than cytochrome P450 metabolism. An important group of conjugation reactions are catalysed by the uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGTs); to date at least 10 different UGT isoforms have been identified. The UGTs are not only involved in the metabolism of many drugs [e.g. morphine, paracetamol (acetaminophen)] but also capable of the biotransformation of important endogenous substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Isoform specificity for these substrates has, however, not been fully characterised. Serious adverse events associated with chloramphenicol toxicity in the neonate have highlighted the importance of developmental changes in UGT activity. However, isoform-specific differences preclude the generalisation of a simple developmental pattern for UGT activity. UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug. However, no general developmental pattern for the individual UGT isoforms which might be of value for the clinician is currently available. Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A gene, which reduces bilirubin glucuronidation, leading to genetic hyperbilirubinaemia (the Crigler-Najjar and Gilbert's syndromes), but also for 3 other UGT isoforms. However, the impact of these genetic differences on drug metabolism remains to be established because of overlapping isoform specificity of the drugs studied, as well as a lack of specific probe substrates to test the activity of individual UGT isoforms in relation to these gene mutations. Clearly, an information gap exists regarding the developmental and genetic aspects of UGT regulation and its potential impact on therapy. More research is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation of scientific information into clinically applicable knowledge.
Child↗
Cytochrome P450 3A: ontogeny and drug disposition.
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 CYPcontent 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 P-450 Enzyme System↗