Synergistic effects of thyroxine and dexamethasone on enzyme ontogeny in rat small intestine.

The synergistic effects of dexamethasone (DEX) and thyroxine (T4) on the postnatal maturation of the 13-d-old rodent small intestine has been studied. Previous studies have shown that hydrocortisone and T4 produced a synergistic response in enzyme maturation. However, T4 elevates corticosteroid-binding globulin, which reduces the clearance of hydrocortisone. Thus, the apparent synergy between T4 and hydrocortisone may have been due to increased glucocorticoid availability. DEX, which does not bind to corticosteroid-binding globulin, was given (d8-12) at 25 pmol (i.e. 0.01 micrograms)/g body wt/d as established by a dose-response study in which this dose of DEX induced one third the maximum response in sucrase activity. In this way, synergy with T4 (130 pmol/g body wt/d, i.e. 0.1 micrograms/g body wt/d, d 5-12) could still be observed. Glucoamylase, lactase, acid beta-galactosidase, alkaline phosphatase, and sucrase activities were determined in two regions of the small intestine. Overall, the results for the two hormones administered alone showed intestinal maturation to be not significantly affected in the T4 group and partially stimulated in the DEX group. When combined, DEX + T4 synergistically increased jejunal sucrase, ileal glucoamylase, and duodenal alkaline phosphatase, and lowered ileal acid beta-galactosidase. The striking exceptions to the general pattern were two brush border enzymes that normally decline during intestinal maturation, namely ileal alkaline phosphatase and jejunal and ileal lactase. For these enzymes, DEX alone did not elicit precocious maturation, and there was no evidence for a synergistic interaction of these two hormones. Serum corticosterone concentrations also were measured. When corticosterone concentrations were compared with enzyme activity, no correlation was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fetal and maternal corticosterone and corticosteroid binding globulin in the diabetic rat gestation

Delayed fetal lung development is a feature of the diabetic pregnancy. Since fetal glucocorticoids are important in the regulation of lung maturation, we measured corticosterone and corticosteroid-binding globulin binding capacity in streptozotocin-diabetic pregnant rats and their fetuses. Previous studies have demonstrated delayed fetal lung maturation in this animal model. In control fetuses, total corticosterone concentration increased through day 20 of gestation, then declined until day 22 (term). The unbound steroid, which accounted for 5-10% of the total, increased approximately 3-fold from day 18 to term. Corticosteroid-binding globulin binding capacity peaked on day 19 after which it decreased. Maternal total and unbound corticosterone levels and corticosteroid-binding globulin binding capacity remained relatively constant throughout the final week of normal gestation. When compared to controls, fetuses from diabetic pregnancies had significantly lower total corticosterone from day 19 through 22. Corticosteroid-binding globulin binding capacity was also significantly decreased in these fetuses for the last 4 days of gestation. Similar differences were noted in maternal samples. However, no significant differences in unbound, biologically active, corticosterone were seen when diabetic and control groups were compared. Thus, delayed fetal lung maturation observed in fetuses of streptozotocin-diabetic rats is associated with a decrease in total circulating corticosteroid levels late in gestation. However, since unbound corticosteroid levels were similar in fetuses of control and diabetic animals, it is likely that other mechanisms may be responsible for the observed delay in lung development in fetuses of diabetic pregnancies.     

Maturation of caffeine elimination in infancy.

The developmental changes in caffeine elimination were studied in 7 infants aged between 2 1/2 weeks and 6 months. Adult plasma clearance rate of caffeine was achieved at 3 to 4 1/2 months of age. Plasma half-life and elimination rate reached adult levels after 3 to 4 1/2 months and seemed to exceed adult capacity thereafter. No significant changes in apparent volume of distribution were noted. Our data provide some indication of the age in infancy when the low rates of caffeine elimination in the neonate increase to the adult rate.     

Plasma cortisol distribution in the pig from birth to six weeks of age

Plasma levels of cortisol and percent distribution of cortisol among protein-bound (corticosteroid-binding globulin (CBG) and albumin) and unbound forms were measured in naturally born/conventionally reared pigs from birth to 6 weeks of age. Total cortisol and percent unbound cortisol were highest in pigs at birth and decreased (p less than 0.01) in a linear fashion over the sampling period. Percent CBG-bound cortisol was lowest on days 3-21 relative to the peak value seen on day 42. However, actual CBG-bound cortisol was not different after day 1. Percent albumin-bound cortisol was highly correlated with percent CBG-bound cortisol (r = -0.90; p less than 0.001). These results suggest that a rapid shift in cortisol distribution from unbound and albumin-bound forms to that which is bound to CBG occurs by approximately day 28 of age in the neonatal pig.     

Circulating corticosterone in the infant rat: the mechanism of age and thyroxine effects

Infant rats exhibit a marked rise in serum concentrations of corticosterone between postnatal days 12 and 24. As this rise appears to be cued by L-thyroxine, the aim of the current study was to determine the physiological bases of the effects of both age and thyroid status on serum corticosterone. The in vivo response to either adrenocorticotropic hormone (60 mU/g body weight) or dibutyryl 3',5'-cyclic adenylate (0.3 mg/g body weight) increased between 10 and 16 days and was advanced and delayed by hyper- and hypothyroidism, respectively. In contrast, in vitro studies with adrenals from rats aged 10 and 16 days showed no effect of age on either basal or adrenocorticotropic hormone-stimulated production of corticosterone. Chronic administration of exogenous corticosterone to hyperthyroid animals resulted in significantly higher concentrations of serum corticosterone than did an identical administration to hypothyroid animals. As hyperthyroidism was associated with marked elevations in the concentration of corticosteroid-binding globulin and in the extent of binding of corticosterone, these results suggest that the effects of both age and thyroid status on serum concentrations of corticosterone may reflect changes in the metabolic clearance of the hormone.     

Single-dose pharmacokinetics of imipenem in children

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.     

Effects of chronic maternal dexamethasone treatment on the hormones of the hypothalamo-pituitary-adrenal axis in the rat fetus

Different hormones of the hypothalamo-pituitary-adrenal axis (corticotropin-releasing factor, adrenocorticotropic hormone, corticosterone) were measured in brain pieces (stalk, median eminence, hypothalamus), hypophyses, adrenals and plasma of 21-day-old rat fetuses from mothers which were given either plain tap water or water containing dexamethasone acetate (10 micrograms/ml) from day 15 to 21 of gestation. Dexamethasone induced drastic reduction of body weight (-66% vs. controls), severe atrophy of the adrenals (-83%) and a sharp drop in their corticosterone content (-74%). Fetal plasma corticosterone levels were below the lower limit of detection of the competitive corticosteroid-binding globulin (CBG) radioassay (less than 0.01 microgram/ml). Both atrophy and severe reduction of the adrenal activity in fetuses from dexamethasone-treated females were in good correlation with a drastic decrease in plasma adrenocorticotropic hormone (ACTH) levels which were below the lower limit of detection of the radioimmunoassay (RIA) used (less than 10 pg/ml) and a significant reduction in pituitary ACTH content (-93%). The low corticostimulating activity of the fetal hypophyses was associated with a drop in both corticotropin-releasing factor (CRF) hypothalamic content (-57%) and concentration (-67%). The effects of dexamethasone on plasma and pituitary ACTH concentrations in 21-day-old fetuses were compared to those, previously reported, of encephalectomy and decapitation performed on day 16 of gestation. The reported data were consistent with the present results, suggesting both pituitary and hypothalamic sites for the in vivo inhibiting action of dexamethasone on the rat hypothalamic-pituitary-adrenal axis in late gestation.     

Pharmacokinetics and pharmacodynamics of cimetidine and metabolites in critically ill children

Cimetidine and antacids are the mainstays of therapy for the prophylaxis of stress-induced ulceration in critically ill children. Previous cimetidine dosing recommendations have been empiric because of a lack of knowledge about cimetidine disposition kinetics in children. Thirty children, mean age 9 +/- 3.2 years, were admitted to the study with the following primary diagnoses: closed head injury (23 patients), sepsis (four), gunshot wound (two), and bleeding gastric ulceration (one). The mean dose of cimetidine was 26 mg/kg/day, administered intravenously over 15 minutes in four divided doses. Cimetidine disposition was best described by a biphasic elimination curve with t1/2 values for cimetidine, cimetidine sulfoxide, and hydroxymethyl cimetidine of 1.39, 2.6, and 4.7 hours, respectively. Cimetidine plasma concentrations were maintained at greater than or equal to 0.5 microgram/ml for a significantly longer time in patients who received greater than or equal to 20 mg/kg/day. Most patients had a plasma cimetidine concentration below 0.5 to 1.0 microgram/ml 4 hours after infusion. The mean apparent volume of distribution and total body clearance for cimetidine were 1.23 L/kg and 10.4 ml/min/kg, respectively. A significant correlation was found between age and either apparent volume of distribution (r = 0.76, P less than 0.001) or total body clearance (r = 0.75, P less than 0.001). No significant correlation between cimetidine concentrations in either plasma or gastric juice and gastric pH could be determined. However, seven of nine patients who received only cimetidine had a gastric pH of greater than or equal to 4 at 2 hours after infusion when the plasma cimetidine concentration was greater than or equal to 1.0 or the gastric juice concentration was greater than or equal to 2.0 microgram/ml. The mean gastric pH was 2.2 at 6 hours, when plasma and gastric juice concentrations of cimetidine were greater than or equal to 1.0 microgram/ml. On the basis of our data, a cimetidine dosage of 20 to 30 mg/kg/day administered in six divided doses should provide for average steady-state plasma cimetidine concentrations of 1.3 to 2.0 micrograms/ml.     

Caffeine pharmacokinetics in young and adult dogs

The pharmacokinetics of caffeine were studied in young (age: 1 day, 7 days, 14 days, 30-45 days) and adult dogs following a single intravenous dose of 50 mg/kg. Mean (+/-SE) plasma elimination half life (T1/2) was 47.5 (+/-5.35) h in 1-day-old puppies, as opposed to 6.66(+/-0.85) h in adult dogs. A rapid decrease in plasma T1/2 values occurred during the first 2 weeks of life. At about 14 days of age caffeine plasma T1/2 was similar to that of adults. The volume of distribution was greatest (0.94+/- 0.03 liters/kg) and the total body clearance was smaller (2.81 +/- 0.73 liters/kg/min X 10(-4)) in the 1-day-old animals. The much smaller body clearance of caffeine in the newborn as compared to the adult dog could be due to a lower rate of metabolism and/or renal excretion of this drug in the young.     

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.     

Pharmacokinetic study of valproic acid in a neonate

Valproic acid was administered to a neonate (gestational age of 39 weeks) at 24 days post partum in an initial single dose of 7.5 mg/kg. Multiple serum samples were collected for 24 hours post dose. Valproic acid was continued and the study was repeated in the same child at 6 months of age at which time the dose had been increased to 13.5 mg/kg (27 mg/kg/day). Serum samples were collected for 12 hours post dose in this second study. A one-compartment model was assumed for calculation of the relevant pharmacokinetic parameters. The half-life (t 1/2) at 24 days of age was 17.2 hours, clearance (Cl) 0.18 ml/min/kg, and volume of distribution (Vd) 0.28 liter/kg. This t 1/2 was less than reported values in neonates younger than 10 days but longer than the average t 1/2 in adults. At 6 months of age, clearance had increased to 0.53 ml/min/kg, t 1/2 had decreased to 7.5 hours, while Vd was relatively unchanged (0.34 liter/kg). Factors possibly causing these changes include hepatic enzyme maturation and concomitant administration of anticonvulsant drugs.     

Age-dependent differences in the relationship between plasma and brain extracellular fluid concentrations of magnesium after MgSO4 infusions in miniswine.

Magnesium is a potential neuroprotective agent in the treatment of head injury and ischemia whose efficacy is likely determined by increases in brain extracellular fluid (ECF) magnesium, which in turn depends on its concentration in plasma. The objectives of this study were to: 1) examine the effects of increasing plasma magnesium concentration ([Mg]plasma) to 4-6 mM on brain ECF magnesium concentration ([Mg]ECF) and 2) determine whether maturational changes occur in the transfer of magnesium into brain ECF for newborn and more mature (approximately 1 month old) miniswine. Increases in [Mg]plasma by systemic administration of MgSO4 resulted in similar maximal elevations in brain [Mg]ECF for both age groups (193+/-76% versus 253+/-106% of control for newborn and 1-month-old miniswine, respectively). Calculations of half-lives (t1/2) for the increase and decrease in magnesium concentration (t1/2 uptake and t1/2 clearance) were used to characterize magnesium kinetics in plasma and brain ECF. Plasma magnesium uptake was shorter in 1-month-old (t1/2 = 11.1+/-0.9 min) compared with newborns (12.9+/-1.7 min, p < 0.05). The faster increase in [Mg]plasma probably contributed to a faster uptake of brain [Mg]ECF in 1-month-old compared with newborn swine (t1/2 uptake = 27.9+/-12.8 versus 46.0+/-20.9 min, respectively, p < 0.05). Although plasma magnesium clearance was shorter in 1-month-old swine compared with newborn (t1/2 = 34.3+/-7.0 versus 74.7+/-33.7 min, respectively, p < 0.05), the clearance of magnesium from the brain ECF was similar for each age group. Reductions in blood pressure and heart rate occurred during hypermagnesemia and were similar in each age group. This study shows that acute elevations in [Mg]plasma to 4-6 mM result in similar relative increases in brain [Mg]ECF for both newborn and 1-month-old miniswine. However, there are maturational differences, as demonstrated by the faster rate of magnesium uptake into the ECF observed in the older miniswine.     

Pharmacokinetics and metabolism of trimethoprim in neonatal and young pigs

The pharmacokinetics and metabolism of trimethoprim (TMP) was studied in newborn, 1 and 8-week-old piglets after intravenous administration of 5 mg/kg. Kinetic parameters were calculated using a two-compartment open model. Steady-state volume of distribution increased from 0.78 L/kg at birth to 1.32 L/kg at 1 week, and 1.83 L/kg at 8 weeks due to changes in plasma protein binding and tissue accumulation. Elimination half-life decreased from 485 minutes at birth to 224 minutes at 1 week, and 120 minutes at 8 weeks leading to a rise in body clearance from 1.18 to 11.8 ml/min/kg during the same period. Urinary excretion data indicated that the increase in body clearance reflects maturational changes in both metabolic capacity and renal function. Metabolism was the main contributor to the elimination of TMP at all ages, although the major metabolic pathway, O-demethylation and subsequent conjugation, was only slightly developed at birth. The capacity to form conjugates with either glucuronic acid or sulphate appeared to be at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excreted as conjugates in all groups.     

Plasma protein binding of theophylline during development in the rabbit.

The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (THu), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). THu, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 microEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between THu and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.     

Dopamine pharmacokinetics in critically ill newborn infants

To compare clinical responses with plasma concentrations of dopamine and to compare dopamine pharmacokinetics in infants of different gestational age or clinical condition, dopamine was administered under carefully controlled conditions of dose and rate of infusion. The dose was increased stepwise from 1 to 2, to 2 to 4, and 4 to 8 micrograms/kg/min. Plasma concentrations of catecholamines, including dopamine, were compared with blood pressure, heart rate, and Doppler cardiac output. The data were analyzed to determine the threshold or minimal plasma concentration of dopamine necessary to produce discernible effects. Plasma clearance rate was calculated from steady-state plasma concentrations. The average threshold for increases in mean arterial pressure was 50% below that for increases in heart rate. Improvements in arterial pressure were noted before and at lower thresholds than for increases in heart rate. Serial echocardiographic data showed dose-dependent increases in cardiac output and stroke volume without significant change in heart rate or systemic vascular resistance. Thresholds and plasma clearance values were similar in infants of gestational age 27 to 42 weeks and birth weights 900 to 4300 g. Administration of dopamine at initial dosages lower than commonly recommended, followed by incremental increase in dose, may be associated with improved left ventricular performance with avoidance of undesirable tachycardia and arrhythmias.     

Pharmacokinetics and adverse effects of amphotericin B in infants and children

The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.     

The influence of parity, age and maturity of pregnancy on antimicrobial proteins in human milk

Sequential samples of colostrum, transitional and mature milk from 47 women were investigated to determine the concentrations of 11S IgA, IgG, IgM, alpha 1-antitrypsin, lactoferrin, lysozyme, B1A globulin (C3) and B1E globulin (C4) by single radial immunodiffusion. These were all found to be high in colostrum with a decline in concentration as lactation proceeds although a wide variation in concentration was noted between different individuals at any given post-partum time interval. For each time interval considered, parity, age and maturity of pregnancy did not appear to influence significantly the variation in protein concentrations. Statistical analyses of the results obtained from samples taken during the first four days of lactation, when protein concentrations were highest, showed that parity and age did influence the variation in antimicrobial protein concentrations when examined using an analysis of variance but significantly higher concentrations of protective proteins were not consistently seen in the milk from any one or more parity or age groups. Mean concentrations of all proteins excluding IgA were found to be greater in those women delivering before their expected date of confinement during the first four days of lactation. This was statistically significant for C3 and C4 and approaching significance (p less than 0.08) for alpha 1-antitrypsin.     

Pharmacokinetics and safety of ceftriaxone in the neonate

The pharmacokinetics and safety of ceftriaxone were examined in 39 neonates who required antibiotics for clinically suspected sepsis. The drug was administered as a once daily dose of 50 mg/kg by the intravenous (IV) or intramuscular (IM) route. Ceftriaxone was assayed in 49 series of blood samples, 3 samples of cerebrospinal fluid (CSF) and 15 samples of urine by a microbiological technique. Blood was collected before, during and after treatment for biochemical analysis. Routine haematological investigations were also monitored. There was no significant differences between the maximum plasma concentrations following IV (153±39 mg/l) or IM (141±19 mg/l) administration (first dose). The mean elimination half-life, total body clearance, and volume of distribution following the first dose were 15.4±5.4 h, 0.28±0.12 ml/min per kg and 325±59 ml/kg respectively. Clearance increased with increasing postnatal age and body temperature (P<0.0002) and decreasing plasma creatinine concentration (P<0.005). Increasing plasma protein concentration was associated with a decrease in volume of distribution (P<0.001). There were no drug-associated changes in any of the biochemical or haematological parameters examined. Ceftriaxone is a safe and well tolerated antibiotic for use in the treatment of newborn sepsis and possibly meningitis. A once daily administration of 50 mg/kg by the IV and IM routes provides satisfactory plasma concentrations throughout the dosage interval whilst avoiding accumulation.Abbreviations IV intravenous - IM intramuscular - CSF cerebrospinal fluid - Cmax maximum, serum concentration - T1/2 serum elimination half-life - Cl total body clearance - Vd volume of distribution - Tmax time to maximum serum concentration     

Plasma 17OH-progesterone concentrations in newborn infants.

Plasma concentrations of 17OH-progesterone were determined in 60 normal newborn infants aged between 3 and 36 hours. Mean levels decreased rapidly during this time after removal of the placental contribution of this steroid. A further 70 normal infants, studied between ages 2 and 7 days, showed a mean plasma 17OH-progesterone concentration of 3.5 nmol/1 (1.2 ng/ml). By comparison, plasma concentrations in untreated infants with congenital adrenal hyperplasia were markedly raised. At 36 hours of age, there was an obvious difference between plasma levels of this steroid in normal and affected infants. Determination of plasma 17OH-progesterone concentrations are valuable in the evaluation of disorders of sexual differentiation and electrolyte balance in newborn infants, provided due care is given to the timing of sample collections.     

Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant

The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575–1450 g; gestational age: 26.8 weeks, range: 22–31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean ± SEM) show that apparent volume of distribution (AVd) was 62.1 ± 3.9 ml/kg, plasma t _1/2 beta was 30.5 ± 4.2 h, elimination rate constant (k_el) was 0.032 ± 0.004 h^-1plasma clearance was 2.06 ± 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 ±11.1 mg/1. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 ± 54.5 mg/1 and 113.6 ± 58.2mg/1, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 ± 0.39%, n = 26) compared to adult plasma protein (mean ± SE = 98.73 ± 0.31%, n = 8, p < 0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.