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Biomedical subjects

G L Kearns

Publications and source records attributed to G L Kearns.

At least 55 records · Page 3Linked to original sources
PubMed1999

Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine.

Cytochrome P-450 (CYP) 2D6 is responsible for the biotransformation of over 35 pharmacologic agents. In the process of studying CYP2D6 we identified phenotype-genotype discordance in two individuals receiving terbinafine. This prompted evaluation of the potential for terbinafine to inhibit CYP2D6 in vitro. Human hepatic microsomes and heterologously expressed CYP2D6 were incubated with terbinafine or quinidine and the formation of dextrorphan from dextromethorphan was determined by HPLC. Additionally, preliminary conformational analyses were conducted to determine the fit of terbinafine into a previously described pharmacophore model for CYP2D6 inhibitors. The apparent Km and Vmax of dextrorphan formation from four human hepatic microsome samples ranged from 5.8 to 6.8 microM and from 172 to 300 pmol/min/mg protein, respectively. Values of Km and Vmax in the heterologously expressed CYP2D6 system averaged 6.5 +/- 2.1 microM and 1342 +/- 147 pmol/min/mg protein, respectively. Terbinafine inhibited dextromethorphan O-demethylation with an apparent Ki ranging from 28 to 44 nM in human hepatic microsomes and averaging 22.4 +/- 0.6 nM for the heterologously expressed enzymes. Results of quinidine in these systems produced values for Ki ranging from 18 to 43 nM. Such strong inhibition of CYP2D6 by terbinafine would not have been predicted by the previously proposed pharmacophore model of CYP2D6 inhibitors based on molecular structure. Terbinafine is a potent inhibitor of CYP2D6 with apparent Ki values well below plasma and tissue concentrations typically achieved during a therapeutic course. This agent needs to be evaluated in vivo to determine the impact of CYP2D6 inhibition by terbinafine on the metabolism of concomitantly administered CYP2D6 substrates.

Cytochrome P-450 CYP2D6↗
PubMed1999

Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity.

We evaluated the utility of the 3-methoxymorphinan/dextromethorphan (3MM/DM) urinary ratio to reflect baseline CYP3A activity, and its ability to discriminate moderate CYP3A inhibition during fluvoxamine therapy. For 4 months, oral dextromethorphan 30 mg and intravenous midazolam 0.025 mg/kg were administered to nine men every 14 days, and to 10 premenopausal women during the follicular and luteal phases of their menstrual cycles. Phenotyping during the first 3 months or cycles established baseline CYP3A activity. During the fourth month, individuals were given fluvoxamine 150 mg/day. CYP3A activity was expressed as both the urinary 3MM/DM molar ratio and midazolam plasma clearance (MDZ CL). 3MM/DM ratios were independent of dextromethorphan CYP2D6 phenotype (r = 0.13, P = 0.6). Intraindividual variability in baseline CYP3A activity (median, 25-75th percentile), as determined by coefficients of variation, was 48.3% (36.8-68.8%) for 3MM/DM and 10.3% (8.3-11.8%) for MDZ CL. No significant correlation between 3MM/DM and MDZ CL either at baseline (r = -0.22, P = 0.4) or during fluvoxamine therapy (r = -0.15, P = 0.6) was noted. With fluvoxamine 150 mg/day, median percentage change in the 3MM/DM ratios was -50.0% (-105.6-6.0%; P = 0.7), and median percentage change in MDZ CL was -33.7% (-27.0-39.3%; P < 0.0001). Only MDZ CL consistently indicated moderate inhibition of hepatic CYP3A activity. In addition, there was a lack of correlation between the magnitudes of fluvoxamine-induced change in 3MM/DM and MDZ CL (r = 0.41, P = 0.1). The large intraindividual variability of the 3MM/DM urinary ratio, as well as the inability to discriminate moderate CYP3A inhibition, makes this a suboptimal method for accurately assessing CYP3A activity.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Pharmacokinetics of metoclopramide in neonates.

Despite its wide use as a prokinetic agent in neonates and infants with gastroesophageal reflux (GER), the pharmacokinetics of metoclopramide have not been characterized in this pediatric subpopulation. A single-dose pharmacokinetic study of oral metoclopramide (0.1 to 0.15 mg/kg) was performed in 10 fasted premature infants (weight 1.1 to 3.2 kg) ranging from 31 to 40 weeks postconceptional age. Metoclopramide was quantitated from repeated blood samples (n = 9 over 24 hours) by high-performance liquid chromatography. A one-compartment open model with first-order absorption best described the plasma concentration-time data. No correlations were observed between gestational, postnatal, or postconceptional age and any of the pharmacokinetic parameters studied. Comparison of the pharmacokinetic parameters from the study cohort and those reported previously from a similar study of older infants revealed no statistically significant differences. However, a prolonged apparent plasma clearance (Cl/F) of metoclopramide was observed in 30% of the infants studied, and the mean Cl/F and apparent steady-state volume of distribution (Vdss/F) were approximately 1.4- and 2.1-fold higher, respectively, than values reported in previous studies of metoclopramide disposition in adults. These data suggest that metoclopramide pharmacokinetics may exhibit a developmental dependency. Thus, a metoclopramide dose of 0.15 mg/kg given orally every 6 hours is recommended for the initiation of prokinetic therapy with this agent in infants who are < or = 31 weeks postconceptional age.

Administration, Oral↗
PubMed1998

Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation.

The pharmacokinetics and pharmacodynamics of ranitidine were studied in 13 term neonates with stable renal and hepatic function who were treated with extracorporeal membrane oxygenation (ECMO). Ranitidine was initially administered as a single 2 mg/kg dose over 10 minutes and intragastric pH was monitored to determine response. Within 90 minutes after administration of ranitidine, intragastric pH for all of the patients whose initial reading was < or = 4 had increased to > 5. Intragastric pH remained > 4 for a minimum of 15 hours. Mean +/- 1 standard deviation elimination half-life was 6.61 +/- 2.75 hours, and 41.5 +/- 22.2% of the single dose was eliminated in urine within 24 hours. Total plasma clearance of ranitidine correlated well with estimated glomerular filtration rate. Twenty-four hours after the initial dose, a continuous infusion of ranitidine (2 mg/kg/24 hr) was started and continued for 72 hours or until ECMO was discontinued. Eleven patients completed 48 hours of continuous infusion and seven completed all 72 hours. Plasma clearance and elimination half-life were determined from steady-state plasma ranitidine concentrations 24, 48, and 72 hours after the start of the infusion. There were no significant differences in clearance between these intervals. These data suggest that for term neonates with stable renal and hepatic function, ranitidine does not need to be administered more frequently than every 12 hours. A continuous infusion of 2 mg/kg/24 hours maintained intragastric pH above 4 in more than 90% of our patients, and in our opinion is the preferred method for delivering ranitidine to term neonates undergoing ECMO who require H2 antagonists. Response to therapy should be monitored by repeated measurement of gastric pH and the dose should be adjusted accordingly.

Extracorporeal Membrane Oxygenation↗
PubMed1998

Absence of effect of terbinafine on the activity of CYP1A2, NAT-2, and xanthine oxidase.

Terbinafine is an allylamine antifungal agent used for the treatment of onychomycosis. It has previously been reported to interact with caffeine and is metabolized in part by the cytochrome P450 systems. This open-label, randomized, crossover study was conducted to examine the effect of terbinafine on the activity of cytochrome P450 1A2 (CYP1A2), N-acetyltransferase (NAT-2), and xanthine oxidase (XO). Twelve healthy nonsmoking adult volunteers were enrolled. Each received single doses of caffeine (100 mg), and urine was collected for a 16-hour period with and without multiple-dose oral administration of terbinafine (250 mg daily for 3 days). Study periods were separated by a 4-week washout period. Urinary caffeine metabolite ratios were used to assess CYP1A2, NAT-2 and XO activity. Comparison of mean metabolic ratios for treatment with and without terbinafine indicated that terbinafine did not appear to alter the activity of CYP1A2, NAT-2, or XO, all of which regulate the biotransformation of caffeine.

Adult↗
PubMed1998

Serum sickness-like reaction to cefaclor: lack of in vitro cross-reactivity with loracarbef.

OBJECTIVES: A lymphocyte-based in vitro rechallenge technique was used to examine the potential for cross-reactivity between loracarbef and cefaclor in children who had had adverse reactions to cefaclor. STUDY DESIGN: The study cohort included 10 patients (2.2 +/- 1.1 years old) with a serum sickness-like reaction to cefaclor, five patients (4.1 +/- 4.6 years old) with immediate-type hypersensitivity reactions to the drug, and five patients (1.5 +/- 0.9 years old) who had a delayed hypersensitivity reaction to cefaclor without joint involvement (i.e., not a serum sickness-like reaction). Peripheral blood mononuclear cells were isolated from each patient and were exposed to cefaclor, loracarbef, and the metabolites of each generated with phenobarbital-induced murine hepatic microsomes. RESULTS: Among patients with cefaclor-associated serum sickness-like reactions, lymphocyte killing (expressed as percentage cell kill above baseline) in the presence of cefaclor metabolites (83.6% +/- 42.2%) was significantly (p < 0.02) higher than that observed among the patients with either immediate-type (1.1% +/- 2.4%) or delayed hypersensitivity (0%) reactions. In contrast, loracarbef did not produce significant in vitro cytotoxicity among any of the patient subgroups. Our in vitro evidence was supported at therapeutic rechallenge with loracarbef among three children with cefaclor-associated serum sickness-like reactions who tolerated a full course of therapy without adverse reactions. CONCLUSION: The metabolite-mediated cytotoxicity associated with cefaclor among patients who had had serum sickness-like reactions after therapeutic administration of the drug was not shared with loracarbef. The extent to which the apparent lack of in vitro cross-reactivity between cefaclor and loracarbef may be predictive of clinical cross-reactivity is not known.

Cefaclor↗
PubMed1998

Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping.

OBJECTIVE: To evaluate intraindividual variability and the effects of sex and menstrual cycle phase on the activity of cytochrome P450 1A2 (CYP1A2), N-acetyltransferase 2 (NAT2), and xanthine oxidase. METHODS: Ten white men were given 2 mg/kg caffeine orally every 14 days for 3 months. The same dosage of caffeine was given to 10 premenopausal white women during the midfollicular and midluteal phases of three complete menstrual cycles. Phenotype was determined with urinary caffeine metabolite ratios. RESULTS: For CYP1A2, mean metabolic ratio (+/- SD) was 5.97 +/- 2.78 during the midfollicular phase and 5.32 +/- 1.99 during the midluteal phase (p = 0.2). For extensive and poor metabolizer of NAT2. Mean midfollicular phase metabolite ratios were 0.71 +/- 0.060 and 0.37 +/- 0.030, and mean midluteal phase metabolite ratios were 0.69 +/- 0.076 and 0.39 +/- 0.053 (p = 0.9). For xanthine oxidase, mean midfollicular phase metabolite ratio was 0.63 +/- 0.06 and mean midluteal phase metabolite ratio was 0.63 +/- 0.05 (p = 0.3). Among the men, mean CYP1A2, NAT2 rapid and slow acetylator, and xanthine oxidase indices were 9.42 +/- 10.18, 0.66 +/- 0.021, 0.31 +/- 0.056, and 0.64 +/- 0.03. There were no differences in metabolite ratios between men and women for CYP1A2, NAT2 extensive metabolizers, or xanthine oxidase. A statistically significant sex difference was found for poor metabolizers of NAT2 (p < 0.05). Median coefficients of variation for CYP1A2, NAT2 extensive and poor metabolizers, and xanthine oxidase ratios were 16.8% (range, 4.5% to 49.3%), 2.9% (range, 2.2% to 4.7%), 13.4% (range, 7.5% to 27.2%), and 4.5% (range, 2.3% to 13.0%). CONCLUSION: Stratification by menstrual cycle phase or sex need not be performed for pharmacokinetic or clinical investigations of substrates for CYP1A2, NAT2, or xanthine oxidase in which the subject are adults.

Adult↗
PubMed1998

Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.

OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.

Acetyltransferases↗
PubMed1998

Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children.

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic-pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (microgram/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and Sigmoid Emax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlax, k alpha, beta, T1/2 beta, AUC0-infinity, Vd/F, and Clp/F) were not different than those reported previously, except the APAP k alpha was significantly lower. The link component yielded keos of 0.58 +/- 0.06 (mean +/- SE), 0.70 +/- 0.11 and 0.57 +/- 0.11 hr-1 for APAP, IBU05, and IBU10, respectively; the Sigmoid Emax component yielded EC50s (microgram/ml) and sigmoidicity (gamma) of 4.63 +/- 0.39 and 3.98 +/- 0.42 for APAP, 11.33 +/- 1.35 and 3.97 +/- 0.58 for IBU05 and 12.83 +/- 1.89 and 4.27 +/- 0.63 for IBU10. On visual inspection of the efficacy-time profiles of the febrile children, a number of them had an apparent linear function (slope; delta degree C/hr) and/or a sinusoidal cyclic function "confounding" standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (delta degree C/hr) and/or a sinusoidal cyclic function to the Sigmoid Emax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual delta degree Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBU AUC0-infinity was confirmed; doubling the dose from 5 to 10 mg/kg increased the AUC0-->infinity by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p = 0.03) contribution of Tempi (but not age) on the value of the slope function was found. There was no consistent effect of age or Tempi on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age and Tempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, and Tempi interacted with beta in a significant multiple linear relationship with AUC0-infinity. The effects of IBU dose, age, and Tempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified Sigmoid Emax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition to Tempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Acetaminophen↗
PubMed1998

Cefpodoxime pharmacokinetics in children: effect of food.

BACKGROUND: Cefpodoxime, an oral third generation cephalosporin antibiotic, is used for the treatment of acute upper respiratory tract infection caused by susceptible bacteria in children 5 months to 12 years of age. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (10 mg/kg) of cefpodoxime proxetil oral suspension in children, under fed and fasted conditions. METHODS: Seventeen children (8.4 months to 12.2 years old, seven female) participated in this study. Each subject received a single 10-mg/kg dose of cefpodoxime proxetil oral suspension, after a predose fast and again coadministered with food. Repeated blood samples (n=10) were obtained during 12 h postdose and cefpodoxime was quantified from plasma by high performance liquid chromatography. Plasma concentration vs. time data were curve fit for each subject with a nonlinear weighted least squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. RESULTS: Cefpodoxime disposition was best characterized using a one-compartment open model with first order absorption. The area under the plasma concentration vs. time curve, Cmax and Ke were not significantly different between fed and fasted conditions. However, Tmax was significantly prolonged (fed=2.79+/-1.10 h vs. fasted=1.93+/-0.54 h) and Ka was significantly smaller (fed=0.42+/-0.14 h(-1) vs. fasted=0.81+/-0.72 h(-1)) in the fed state. CONCLUSIONS: Administration of cefpodoxime in the presence of food affected the rate but not the extent of absorption. Cefpodoxime proxetil oral suspension can be administered without regard to meals in children 6 months to 12 years of age.

Area Under Curve↗
PubMed1998

Hypokalemia in an asthmatic child from abuse of albuterol metered dose inhaler.

A case of albuterol abuse by a pediatric patient with the development of hypokalemia with electrocardiographic changes is presented. The hypokalemic effects of beta2-agonists are discussed in regard to the production of significant cardiac symptoms. Additionally, guidance regarding the evaluation of similar patients presenting in the emergency department is provided.

Adrenergic beta-Agonists↗
PubMed1998

Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping.

Intraindividual variability and the effects of menstrual cycle phase on CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women during the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection. Ten women and nine men were extensive metabolizer phenotypes, and one man was a poor metabolizer phenotype (confirmed by genotyping). There was no difference in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728+/-0.00717) and mid-luteal (0.00745+/-0.00815) phases of the menstrual cycle (P = 0.88). Also, no significant difference was found in the intraindividual variability of the metabolic ratios between the two phases (P = 0.80). No statistically significant sex difference in CYP2D6 activity was found between men (0.00537+/-0.00431) and women (0.00737+/-0.00983) extensive metabolizers (P = 0.84). For all individuals, intraindividual variability in dextromethorphan ratios ranged from 12.1-136.6% with a median of 36.7%. Because hormonal fluctuations within the mid-follicular and mid-luteal phases of the menstrual cycle do not appear to affect CYP2D6 activity, pharmacokinetic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabolic ratios may fluctuate an average of 37%, repeat baseline and treatment phenotyping assessments should be obtained for accurate determination of a given drug's effect on CYP2D6 activity when measured by dextromethorphan.

Adult↗
PubMed1998

Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution and effect of food.

Pleconaril is an orally active broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (200 mg) of pleconaril oral solution in fed and fasting humans. Twelve healthy adult subjects (18.7 to 39 years of age) participated in this study. Each subject received a single 200-mg dose of pleconaril oral solution, both coadministered with a standard English breakfast and following a 10-h predose fast. There was a minimum 7-day washout period between pleconaril doses. Repeated blood samples (n = 10) were obtained over 24 h postdose, and the pleconaril level in plasma was quantified by gas chromatography. Plasma concentration-versus-time data were curve fitted for each subject by using a nonlinear weighted least-squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. Pleconaril disposition was best characterized by a one-compartment open model with first-order absorption. The apparent bioavailability of pleconaril oral solution was significantly increased with the administration of food. The area under the concentration-time curve and maximum concentration of pleconaril in plasma achieved following the standard English breakfast (i.e., 9.08 +/- 3.23 mg/liter . h and 1.14 +/- 0.58 mg/liter, respectively) were 2.2- and 2.5-fold higher, respectively than those achieved in the fasting state (i.e., 4.08 +/- 2.74 mg/liter . h and 0.46 +/- 0.30 mg/liter, respectively). Mean plasma pleconaril concentrations 12 h after a single 200-mg oral dose (fed, 0.25 +/- 0.2 mg/liter; fasting, 0.11 +/- 0.10 mg/liter) in healthy adults remained greater than that required to inhibit more than 90% of the enteroviruses in cell culture (i.e., 0.07 mg/liter). To enhance the oral bioavailability of pleconaril, coadministration with a fat-containing meal is recommended.

Administration, Oral↗
PubMed1998

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients.

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.

Adult↗