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Biomedical subjects

K L Brouwer

Publications and source records attributed to K L Brouwer.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phase I trial of a 96 h paclitaxel infusion with filgrastim support in refractory solid tumor patients.

A phase I study of a 96 h paclitaxel infusion with filgrastim support was performed to determine the toxicity, maximum-tolerated dose (MTD) and pharmacokinetics in patients with refractory solid tumors. In this phase I trial, the initial paclitaxel dose was 140 mg/m2/96 h followed by filgrastim (5 microg/kg/day s.c.) beginning 24 h after the paclitaxel and continued until granulocyte recovery. Cycles were repeated every 21 days. Patients with refractory solid tumors were eligible; however, only one previous chemotherapy regimen was allowed. The dose of paclitaxel was escalated by 20 mg/m2/96 h in subsequent cohorts until dose-limiting toxicity (DLT) occurred. Pharmacokinetic analysis was performed by quantitating paclitaxel concentrations at baseline, 24, 48, 72 and 96 h after the start of the paclitaxel infusion. Twenty-one patients were entered into this trial of which 19 were evaluable. A total of 52 treatment cycles were administered. DLT was seen in two of four patients at 200 mg/m2/96 h, and consisted of diarrhea, mucositis and granulocytopenic infection. The MTD of the 96 h paclitaxel infusion was 180 mg/m2 with filgrastim support. Mucosal and granulocyte toxicity were correlated with steady-state paclitaxel concentrations (Css) greater than 0.100 micromol/l. In the presence of liver function test 1.5 times or lower than normal, metastatic liver disease did not alter paclitaxel Css. Objective responses were observed in non-small cell lung cancer, small cell lung cancer and melanoma. The recommended phase II dose of paclitaxel infused over 96 h with filgrastim support is 180 mg/m2. Paclitaxel Css correlate with mucosal and granulocyte toxicity. In the presence of normal enzymatic function, metastatic liver disease does not affect paclitaxel clearance.

Adult↗
PubMed1997

Airway deposition and clearance and systemic pharmacokinetics of amiloride following aerosolization with an ultrasonic nebulizer to normal airways.

STUDY OBJECTIVES: Airway epithelial ion transport is an important component of the airway defense mechanism, and new therapies that target ion transport are being developed. Amiloride is an example of such a new drug, exerting a dose-dependent action to inhibit Na+ transport. Amiloride may be useful in cystic fibrosis, blocking the characteristic airway epithelial Na+ hyperabsorption that occurs in the disease. To evaluate airway and systemic delivery of amiloride via an ultrasonic nebulizer (Omron NE-UO7), we measured the airway surface concentrations of amiloride in normal volunteers via a novel approach, together with the systemic pharmacokinetics of amiloride. DESIGN: Direct measurement of airway surface liquid, plasma, and urine amiloride concentrations following ultrasonic nebulization. PARTICIPANTS/INTERVENTIONS: Seven normal subjects were studied in the General Clinical Research Center of the University of North Carolina. Following inhalation with amiloride (1 mg/mL, 4.5 mL) for approximately 12 min, a bronchoscopy was performed. Amiloride deposition and clearance from airway surfaces over 1 h were evaluated by transbronchoscopic sampling using preweighed filter papers. Pulmonary and systemic absorption was assessed by measuring drug concentrations in blood and urine. RESULTS: The mean volume aerosolized was 3.5+/-0.3 mL during 12 min of aerosolization time; the mean initial concentration of amiloride on airway surfaces after nebulization was 1.6 x 10(-4) mol/L, with an elimination half life of approximately 23 min. Peak plasma concentrations of amiloride (30 min, 3.36+/-0.70 ng/mL) suggest early absorption across lung surfaces, rather than via the GI route. Mean urinary excretion of amiloride over 72 h was 0.63+/-0.07 mg, with 87% excreted in the first 24 h. CONCLUSIONS: The ultrasonic nebulizer rapidly delivers amiloride to normal conducting airways as assessed by the transbronchoscopic sampling technique. Early blood concentrations of amiloride probably reflect initial absorption across lung surfaces and are a useful index of the efficiency of the machine.

Absorption↗
PubMed1997

Solid-phase extraction and determination of ranitidine in human plasma by a high-performance liquid chromatographic method utilizing midbore chromatography.

An improved high-performance liquid chromatographic (HPLC) method utilizing solid-phase extraction (SPE) and midbore chromatography was developed for the determination of ranitidine in human plasma. A mobile phase of 20 mM K2HPO4-acetonitrile-triethylamine (87.9:12.0:0.1, v/v) pH 6.0 was used with a phenyl analytical column and ultraviolet detection (UV). The method demonstrated linearity from 25 to 1000 ng/ml in 500 microliters of plasma with a detection limit of 10 ng/ml. The method was utilized in a pharmacokinetic study evaluating the effects of pancreatico-biliary secretions on ranitidine absorption.

Anti-Ulcer Agents↗
PubMed1997

A modified residual method to estimate the zero-order absorption rate constant in a one-compartment model.

The objective of this work was to develop a simple residual method to estimate the rate constant for actual or apparent zero-order absorption into a one-compartment model. The method is based on the fact that, in theory, a plot of residuals versus e-Kt is linear for a zero-order absorption process, where K represents the elimination rate constant governing the terminal phase of the concentration-time profile. The apparent absorption rate constant (K0) can be calculated from the slope and intercept of the residual plot. Simulated concentration-time data with superimposed random error (CV = 5, 10, 15%, n = 8), as well as data sets from the literature for hydroflumethiazide and theophylline were analyzed with the proposed method of residuals. Parameters derived with the new technique were compared to both the nonlinear least-squares regression and the Wagner-Nelson method, all of which yield comparable K0 estimates. These results indicate that the proposed method of residuals represents a simple approach for estimating the apparent zero-order absorption rate constant analogous to classic residual analysis for first-order absorption.

Administration, Oral↗
PubMed1997

Hepatic distribution and clearance of antisense oligonucleotides in the isolated perfused rat liver.

PURPOSE: This study was conducted to investigate the impact of backbone modifications on the hepatobiliary disposition of oligonucleotides. METHODS: The disposition of backbone-modified antisense oligonucleotides [phosphorothioate (PS) and methylphosphonate (MP)] of the same base-length and sequence (5'-TAC-GCC-AAC-AGC-TCC-3'), complementary to the codon 12 activating mutation of Ki-ras, was investigated in the isolated perfused rat liver. Livers were perfused for 2 hr: perfusate and bile concentrations were analyzed by HPLC. Hepatocellular distribution was examined by measuring the amount of radiolabeled PS oligonucleotide associated with hepatocytes and Kupffer cells. Protein binding of the PS and MP oligonucleotides was determined in rat serum by ultrafiltration. RESULTS: MP oligonucleotide perfusate concentrations remained constant during the 2-hour perfusion. In contrast, PS oligonucleotide was eliminated slowly by the isolated perfused liver [CI = 1.05 +/- 0.21 mL/min; extraction ratio = 0.06 +/- 0.01]. Uptake of PS oligonucleotide by Kupffer cells appeared to exceed uptake by hepatocytes, based on standard cell separation techniques as well as confocal microscopy. The degree of protein binding in rat serum was greater for the PS oligonucleotide (79.9 +/- 2.2%) than for the MP oligonucleotide (53.0 +/- 4.7%). CONCLUSIONS: Backbone modifications significantly-influence the hepatic clearance of oligonucleotides. Uncharged MP oligonucleotides are not extracted by the isolated perfused rat liver, whereas the charged PS oligonucleotide is processed more readily.

Animals↗
PubMed1997

Heat treatment of human serum to inactivate HIV does not alter protein binding of selected drugs.

Human immunodeficiency virus (HIV) may be transmitted via certain biological fluids, particularly blood. To minimize the risk of accidental exposure, the virus may be inactivated by heat treatment of blood, plasma, or serum samples at 54-56 degrees C for 5 h. The objective of this study was to determine whether heat treatment of human serum alters the protein binding of model compounds. Diazepam, phenytoin, and digitoxin were selected for investigation because they bind to three different sites on human serum albumin (HSA); propranolol also was examined since it binds to both HSA and alpha 1-acid glycoprotein. The unbound fraction of selected drugs was measured by ultrafiltration at 37 degrees C after addition of each compound to either untreated or heat-treated serum. The percentage unbound in serum for diazepam, phenytoin, digitoxin, and propranolol was not significantly different between the untreated and heat-treated samples. Therefore, heat treatment of serum does not appear to alter the binding characteristics at these four binding sites and would not be expected to lead to erroneous unbound concentration estimates and inappropriate adjustments in drug therapy.

Anti-Arrhythmia Agents↗
PubMed1997

In vitro mechanisms of probenecid-associated alterations in acetaminophen glucuronide hepatic disposition.

The effect of probenecid (PRB) on factors regulating the hepatic disposition of acetaminophen glucuronide (AG) was investigated in vitro. Potential interactions in metabolism or binding to cytosolic proteins were examined. In the absence of PRB, AG formation in rat hepatic S9 fractions was saturable (V(max) = 2.77 +/- 0.36 nmol/ min/mg protein; K(M) = 18.0 +/- 0.92 mM). PRB significantly decreased V(max), but not K(M), for AG formation, consistent with noncompetitive inhibition. Various models were fit to the AG formation rate vs. acetaminophen (APAP) and PRB concentration data to elucidate the mechanism of inhibition by PRB. A partial noncompetitive inhibition model (K(i) = 1.10 +/- 0.01 mM) described the data best based on model selection criteria. AG did not bind to the cytosolic protein ligandin (glutathione S-transferase A1). These data indicate that PRB is a potent partial noncompetitive inhibitor of acetaminophen glucuronidation in vitro. PRB-associated alterations in AG hepatic disposition in vivo are not due to altered binding of AG to GSTA1 but may be attributed in part to impaired AG formation.

Acetaminophen↗
PubMed1996

Evidence for reversible sequestration of morphine in rat liver.

The residence of morphine in the systemic circulation is prolonged despite a high systemic clearance, suggestive of significant extravascular sequestration. The present study was conducted to test the hypothesis that morphine binds significantly in tissues, and that the liver plays an important role in morphine binding. [14C]Morphine was administered to male Sprague-Dawley rats 55 min before unlabeled morphine or saline. Blood 14C increased immediately after injection of unlabeled morphine; the area under the blood concentration-time curve (AUC) for 14C increased approximately 2-fold after morphine compared with saline injection. Residual radioactivity in the liver was lower in morphine-treated rats than in controls, suggesting that unlabeled drug displaced [14C]morphine (or a metabolite) from binding sites. To examine this phenomenon more directly, a recirculating isolated perfused liver system was employed. [14C]Morphine was added to the perfusate reservoir 15 min before unlabeled morphine or saline; perfusate and bile samples were collected for 120 min. Upon termination of perfusion, the liver was fractionated to identify the hepatic subcellular fraction(s) in which morphine was sequestered. The perfusate AUC for [14C]morphine was increased approximately 2-fold in response to unlabeled drug, consistent with the in vivo experiment. Morphine was associated preferentially with the cytosolic fraction, and [14C]morphine in all relevant fractions was reduced after administration of unlabeled morphine. In contrast, unlabeled drug had no influence on derived [14C]morphine-3-beta,D-glucuronide. These data are consistent with significant, reversible binding of morphine in hepatic tissue.

Animals↗
PubMed1996

Hepatobiliary disposition of valproic acid and valproate glucuronide: use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions.

Previous work in this laboratory has suggested that the nonlinear disposition of valproic acid (VPA) in the rat may be due to nonlinear distribution of VPA into the liver. The present study was undertaken to elucidate further the hepatobiliary disposition of VPA. VPA (0.1-2 mmol/L) was incubated with isolated rat hepatocytes in vitro. Uptake of [(3)H]-VPA was linear from 10 to 50 seconds, with minimal (<7 percent) biotransformation. The initial velocity of VPA uptake varied in proportion with the extracellular concentration and was temperature independent, suggesting that VPA traverses the hepatocyte membrane predominantly by passive diffusion. In separate studies, the hepatobiliary disposition of VPA (20mg) was examined in the isolated perfused rat liver (IPL). A pharmacokinetic model was developed to describe the influence of phenobarbital on the hepatobiliary disposition of VPA and valproate glucuronide (V-G) in the IPL; all processes governing VPA and V-G disposition appeared to be linear. Acute administration of phenobarbital to the liver (1.12 mg) decreased the rate constant for canalicular egress of V-G (0.0489 +/- 0.0266 vs. 0.164 +/- 0.075 min(-1)). In vivo pretreatment with phenobarbital (75 mg/kg/d x 5 d) before liver isolation decreased the biliary excretion of both VPA (1.06E-04 +/- 0.27E-04 vs. 2.76E-04 +/- 0.45E-04 min(-1)) and V-G (5.63E- 03 +/- 1.98E-03 vs. 1.74E-02 +/- 0.5E-02 min(-1)), and increased the apparent volume of distribution of VPA (84.6 +/- 2.2 vs. 72.3 +/- 2.1 mL). In vivo phenobarbital pretreatment a changed V-G excretion from a formation to an elimination rate-limited process. These results are consistent with phenobarbital-associated impairment of canalicular egress of some organic anions. This work further supports the utility of pharmacokinetic modeling in: (1) determining the rate-limiting steps in hepatobiliary drug disposition and (2) identifying sites of drug interactions within the hepatobiliary system that may not be evident based on conventional mass-balance analysis.

Animals↗
PubMed1996

Age-related changes in valproic acid binding to rat serum proteins in vitro.

The effect of age on the in vitro binding of valproic acid (VPA) to serum proteins was investigated in rats ranging in age from 14 days (preweaning) to 24 months (senescent). The influence of free fatty acid (FFA) and total protein (TP) concentrations on age-related changes in binding was examined. The protein binding of VPA was altered during development and aging. The VPA fraction unbound (fu) at low VPA concentrations was significantly higher in older age groups (12 and 24 months old; fu = 0.26-0.30) than in younger animals (14, 20, and 40 days old; fu = 0.16-0.18). Binding was best described by a model incorporating a saturable and a nonsaturable binding site. Binding affinity at the saturable binding site was lowest at the extremes of age. Changes in binding at either the saturable or the nonsaturable site were not predicted by changes in TP or FFA with age. Changes in nonsaturable binding were marginally associated with age (p = 0.0952). A 3-fold increase in FFA concentrations was necessary to produce a 1.5-fold increase in VPA fu. There was less than a 2-fold difference in FFA concentrations between the age groups (range 0.219-0.379 mmol/L). Thus, the difference in FFA concentrations between the age groups may not have been large enough to cause measurable differences in displacement of VPA from binding sites. Changes in protein binding may contribute to age-related changes in disposition of VPA observed in the rat. Changes in the serum concentrations of specific FFA or proteins may play a role in the altered VPA binding with age, but changes in total FFA or protein concentrations do not account for the age-related differences observed. Further investigation is required to identify the mechanism(s) responsible for age-related changes in binding of VPA to serum proteins measured in vitro.

Age Factors↗
PubMed1996

Physiologic pharmacokinetic modeling of gastrointestinal blood flow as a rate-limiting step in the oral absorption of digoxin: implications for patients with congestive heart failure receiving epoprostenol.

A previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointestinal blood flow (Qg) could alter digoxin systemic bioavailability to a clinically significant extent in severe congestive heart failure (CHF) patients. A series of simulations was conducted in which the influences of apparent gut tissue-to-plasma partition coefficient (Kg) and Qg on digoxin bioavailability were evaluated. Since epoprostenol also increases blood flow to the liver and kidneys, the effect of concurrent increases in regional blood flow to these organs on digoxin bioavailability also was evaluated. A range of Qg was studied from 25 L/h (assumed mesenteric arterial flow in CHF) to 65 L/h (portal venous flow in normal adults), and the area under the simulated digoxin concentration-time curve was used to calculate absolute digoxin bioavailability in each case. Simulations were conducted at a range of Kg from 1 to 50 (physiologically relevant range 5-25). At low values of Kg, the influence of changes in Qg on digoxin bioavailability was minimal. However, as apparent distribution into gut tissue increased (consistent with visceral congestion), the effect of changes in Qg was more substantial. In the physiologically relevant range of Kg, 40-160% increases in Qg were associated with approximately 6-40% increases in digoxin bioavailability. Therefore, the decrease in digoxin oral clearance previously observed in CHF patients receiving epoprostenol may be ascribed to increases in digoxin bioavailability, secondary to epoprostenol-induced increases in Qg.

Adult↗
PubMed1996

Vancomycin serum concentrations in patients with renal dysfunction: a comparison of fluorescence polarization immunoassay and the enzyme-multiplied immunoassay technique.

A study was conducted to determine whether assay-specific quantitative differences exist in the determination of vancomycin serum concentrations obtained from patients with renal dysfunction. Vancomycin serum concentrations were obtained during the first week of therapy for each of three time intervals: 48-96 h, 96-144 h, and 144-192 h after administration of the first dose of vancomycin. Vancomycin serum concentrations were measured using the enzyme-multiplied immunoassay technique (EMIT) and fluorescence polarization immunoassay (FPIA). Twenty patients with an estimated creatinine clearance < 40 ml/min who were receiving intravenous vancomycin were evaluated. Hemodialysis was required in 16 of 20 patients. Fifty samples were included in the data analysis. The mean (+/-SD) serum concentrations obtained with EMIT and FPIA were 10.9 mg/L (+/-5.3) and 12.6 mg/L (+/-5.7), respectively (p = 0.13), and were not statistically different. A linear relationship was observed between EMIT and FPIA (EMIT = 0.89 x FPIA - 0.24; r2 = 0.93). No statistically significant differences were observed in the calculated pharmacokinetic parameters between methods. FPIA and EMIT are comparable methods in determining vancomycin serum concentrations within the first week of vancomycin therapy in patients with moderate to severe renal dysfunction.

Adult↗
PubMed1996

Maternal-fetal pharmacokinetics of methanol.

We undertook the present project to elucidate the physiologic factors that govern methanol delivery to the developing conceptus after maternal methanol exposure, and to develop a physiologically based toxicokinetic model to describe methanol disposition in pregnancy. A multi-experimental approach addressed the goals of this project. Initial experiments characterized the systemic disposition of methanol after intravenous or oral administration to nonpregnant female rats. Methanol absorption from the gastrointestinal tract was rapid (peak concentrations appeared within 1 to 2 hours after administration) and essentially complete (systemic bioavailabilities ranged from approximately 0.6 to 1.0). As anticipated for short-chain aliphatic alcohols, methanol elimination from the systemic circulation was nonlinear due to saturation of the metabolic route or routes responsible for converting methanol to formaldehyde and, ultimately, formic acid. However, a significant parallel linear route of methanol elimination was observed, which accounted for an increasingly significant fraction of total elimination as methanol doses (or systemic concentrations) increased. The disposition of methanol after oral or intravenous administration was similar in pregnant and nonpregnant female rats, regardless of the gestational stage (day 7, 14, or 20 after conception) at which the toxicokinetics of methanol were examined. This observation indicated that data from nonpregnant subjects could be used in the development of the maternal portion of a comprehensive physiologic model for methanol disposition. Parallel experiments in female mice indicated that methanol elimination was approximately twice as rapid in mice as in rats due to a significantly higher maximal velocity for methanol metabolism in the smaller rodent species. As was the case in the rat, relatively small changes in methanol elimination were observed during the course of gestation in pregnant mice. In both species, the rate of methanol metabolism by fetal liver in vitro was less than 10% that of the metabolic rate in adult liver. The kinetics of methanol delivery into the fetal environment were examined by determining amniotic fluid concentrations of methanol after intravenous administration to pregnant rats. The net rate of methanol translocation from maternal blood to amniotic fluid decreased as methanol concentration increased. Although the mechanism of this anomalous result is unknown, it possibly is due to a methanol-induced decrease in blood flow to the fetus.

Administration, Oral↗
PubMed1995

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

Administration, Oral↗
PubMed1995

Gastrointestinal transit and distribution of ranitidine in the rat.

PURPOSE: Ranitidine gastrointestinal distribution was examined in the rat small intestine after oral administration to determine whether intestinal transit or secretion (exsorption) may influence the appearance of secondary peaks in ranitidine serum concentration-time profiles. METHODS: Male Sprague-Dawley rats received ranitidine (50 mg/kg) by oral gavage, and the mass of ranitidine recovered in all small intestinal segments (approximately 12 cm each) was determined 30, 60, 90, or 120 min after administration. In a separate group of anesthetized rats, the small intestine was divided into two segments of equal length that were perfused with normal saline in a single-pass manner. Rats received an escalating, zero-order IV infusion of ranitidine for 30 min, and venous blood and intestinal effluent were collected over 90 min to quantitate ranitidine exsorption. RESULTS: Thirty min after oral administration, > 50% of the recovered ranitidine mass resided in the lower half of the small intestine in all rats. Ranitidine mass in 5 of 16 rats displayed a bimodal distribution with significant amounts of ranitidine recovered from the stomach 60 to 90 min after dosing. Ranitidine exsorption was more efficient from the lower jejunum and ileum than from the duodenum and upper jejunum. However, intestinal secretion of ranitidine was minor (5% of the IV dose). CONCLUSIONS: Ranitidine absorption from the lower ileum contributes significantly to systemic ranitidine concentrations before and during the time of the first concentration maximum. Separation of the drug mass into multiple boluses may contribute to secondary peaks in ranitidine concentration-time profiles. Exsorption did not contribute significantly to ranitidine distribution in the gastrointestinal tract.

Animals↗