Biomedical subjects

T N Tozer

Publications and source records attributed to T N Tozer.

At least 19 recordsLinked to original sources

PubMed1994

Glucocorticoid-dextran conjugates as potential prodrugs for colon-specific delivery: steady-state pharmacokinetics in the rat.

Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side-effects limit chronic glucocorticoid therapy. The dose, and consequently the side-effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid-dextran conjugates in which dexamethasone was attached to dextran (weight-average molecular weight = 72,600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, dexamethasone-succinate-dextran and dexamethasone-glutarate-dextran were administered to two groups of male Sprague-Dawley rats by intragastric infusion. In two additional groups, disodium dexamethasone phosphate and dexamethasone hemisuccinate were each administered by subcutaneous infusion. In a fifth group, dexamethasone was administered by intragastric infusion. All groups were infused for sufficient time for steady state to be achieved. Colon-specific delivery was quantified using a drug-delivery index (DDI) in which steady-state dexamethasone concentrations in the cecum and colon were compared with those measured in blood after separate administrations of dexamethasone and dexamethasone-dextran conjugate. The colonic DDI values for dexamethasone-succinate-dextran and dexamethasone-glutarate-dextran were approximately seven and four, respectively. These values were a result of higher tissue concentrations and lower blood concentrations of dexamethasone after intragastric administration of the conjugates compared to subcutaneous and intragastric administration of dexamethasone. The pharmacokinetics of methyl-prednisolone was also investigated after subcutaneous infusion. Observed cecal and colonic tissue-to-blood ratios of 19:1 and 12:1, respectively, showed that this drug is extensively delivered to the large intestine even after subcutaneous administration.

Animals↗

PubMed1994

Glucocorticoid-dextran conjugates as potential prodrugs for colon-specific delivery: hydrolysis in rat gastrointestinal tract contents.

Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side effects limit chronic glucocorticoid therapy. The dose, and consequently the side effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid-dextran conjugates in which dexamethasone and methylprednisolone were attached to dextran (weight-average molecular weight = 72,600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, the hydrolysis kinetics of the hemiesters (hemiester = glucocorticoid+linker) and dextran conjugates were determined after incubation at 37 degrees C in diluted luminal contents of the gastrointestinal (GI) trace of male Sprague-Dawley rats. The hemiesters were rapidly hydrolyzed in the proximal small intestine (e.g., dexamethasone-hemiglutarate t1/2 = 0.5 h). This rate decreased progressively down the GI tract (t1/2 = 4.8, 54, and 68 h in distal small intestine, cecum, and colon, respectively). The enzyme responsible for hemiester hydrolysis, apparently a type-A alkaline carboxylesterase, is probably of host origin because its activity is highest in the small intestine where bacterial count is low. The dextran conjugates resisted hydrolysis in upper GI tract contents but were rapidly degraded in cecal and colonic contents where the bacterial count is high. The dextran conjugate tested, methylprednisolone-succinate-dextran, was easily hydrolyzed by an endodextranase, indicating that substrate specificity is not lost upon the attachment of glucocorticoid. The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the large intestine for the treatment of colitis.

Anaerobiosis↗

PubMed1994

Pharmacokinetic interaction between benzene metabolites, phenol and hydroquinone, in B6C3F1 mice.

There is strong evidence that metabolites are responsible for adverse effects of benzene. Benzene myelotoxicity, reproduced by coadministering phenol (PH) and hydroquinone (HQ) but not when these benzene metabolites were administered alone, has been postulated to be induced by PH stimulating the myeloperoxidase-mediated oxidation of HQ to the toxic 1,4-benzoquinone in bone marrow. A pharmacokinetic interaction between PH and HQ is also hypothesized to contribute to the observation. Both metabolites are sulfoconjugated and glucuronoconjugated. Sulfoconjugation of phenolic substrates has been shown to approach saturation at high concentrations in rats. Thus, more PH may be converted to HQ and HQ conjugation may be diminished. These effects would increase the amounts of PH and HQ present and result (by further oxidation) in the formation of more 1,4-benzoquinone. To test this hypothesis, we investigated the pharmacokinetics in blood and the recovery of hydroquinone and phenol in urine when the metabolites were administered intraperitoneally alone or in combination at 75 mg/kg each to B6C3F1 mice. The combination resulted in a 2.6-fold increase in the area under the blood concentration-time curve (AUC) of HQ compared to the sum of AUC values observed after administration of each compound alone. The half-life of HQ was also increased from 9 +/- 2 to 15 +/- 3 min. The AUC of PH was increased by a factor of 1.4. The clearance of phenol decreased from 89 +/- 13 ml/min per kilogram when injected alone to 62 +/- 7 ml/min per kilogram after coadministration. A decreased clearance of formation of each conjugate demonstrated that both conjugation pathways were diminished. This interaction may contribute to the observed production of myelotoxicity when these metabolites are coadministered.

Animals↗

PubMed1994

A glucocorticoid prodrug facilitates normal mucosal function in rat colitis without adrenal suppression.

BACKGROUND/AIMS: Glucocorticoids remain the foundation of therapy for acute ulcerative colitis despite systemic side effects that limit their use. Prodrugs that selectively deliver glucocorticoids to the colon may lower the required dose and side effects. The aim of this study was to assess the efficacy of a newly synthesized glucocorticoid-dextran prodrug. METHODS: Novel glucocorticoid-dextran prodrug conjugates in which dexamethasone and methylprednisolone were attached to dextran were synthesized using the dicarboxylic acid linkers, succinate and glutarate. The efficacy of the dextran prodrug conjugates and their free glucocorticoids was tested in an acetic acid-induced model of colitis. Repair of the colitis and mucosal function was assessed by measuring net intestinal fluid absorption, macroscopic ulceration, and myeloperoxidase activity. Glucocorticoid toxicity was evaluated by measuring plasma adrenocorticotropic hormone and serum corticosterone levels. RESULTS: The prodrug dexamethasone-succinate-dextran was nine times more potent and dexamethasone-glutarate-dextran three times more potent than free dexamethasone in accelerating mucosal repair. Similarly, methylprednisolone-succinate-dextran was four times more potent than free methylprednisolone. The dextran prodrug conjugates affected adrenocorticotropic hormone and corticosterone levels only at the highest doses in contrast to free dexamethasone and methylprednisolone, which caused marked adrenal suppression at all doses. CONCLUSIONS: The results show that recently synthesized glucocorticoid-dextran prodrug conjugates can be administered orally to facilitate mucosal repair in rat colitis without adrenosuppression.

Adrenal Glands↗

PubMed1994

Bioequivalence: performance of several measures of extent of absorption.

The determination of the area under the concentration-time curve (AUC) is the method most commonly used by regulatory agencies to assess extent of drug absorption after single-dose administration of oral products. Using simulations, several approaches toward measuring the actual area, in whole or part, were tested. In addition, the performance of the peak concentration (Cmax), usually taken as a measure of the rate of absorption was assessed evaluating extent. Model scenarios for drugs with typical mean characteristics and statistical distributions were investigated. Using different kinetic models of disposition, the time course of the drug concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and Cmax. However, being also sensitive to rate, Cmax as a measure of extent is of limited potential.

Absorption↗

PubMed1994

Bioequivalence: performance of several measures of rate of absorption.

The highest point of the plasma concentration-time profile, Cmax, is currently used by regulatory agencies to assess the rate of drug absorption after single dose administration of oral products. It is, however, quite insensitive, and a number of new measures of rate have been proposed. Using simulations, several approaches toward measuring rate were tested. A set of model scenarios for drugs with typical mean characteristics and statistical distributions was investigated. Using different kinetic models of disposition, the time course of the concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of rate were evaluated by simulating crossover design clinical trials and then determining the probability of declaring bioequivalence as a function of differences in rates of absorption between test and reference formulations. All of the rate measures tested showed a degree of insensitivity to changes in rate and no universally superior measure was found. Indeed, the main conclusion is that the choice of a measure should be based on simulations of the particular situation in a bioequivalence trials.

Computer Simulation↗

PubMed1993

Pentachlorophenol carcinogenicity: extrapolation of risk from mice to humans.

1. Pentachlorophenol (PCP) has been found to be carcinogenic in mice. The objective of this study was to extrapolate to humans the risk of cancer from data obtained in mice using information on disposition, serum protein binding and metabolism of PCP across species. 2. A review of the literature indicates that neither PCP nor a mutagenic metabolite, tetrachlorohydroquinone (TCHQ), has been specifically identified as responsible for the carcinogenicity. In addition, the occurrence of TCHQ as a metabolite of PCP in humans is still questionable. Therefore, cancer risk assessment is performed on the assumption that PCP itself is responsible for the carcinogenicity. 3. For interspecies extrapolation, a new method in which interspecies differences in clearance and serum protein binding are taken into account is used. The method gives estimates of equivalent human doses of PCP which are up to 4 times smaller than those obtained using body surface area. For both interspecies extrapolation methods, the estimated virtually-safe doses of PCP are smaller than the average daily intakes reported in groups of subjects nonspecifically exposed to PCP. Corresponding extra risks of cancer for lifetime exposure are from 20 to 140 times greater than the acceptable extra risk (10(-6)). The results obtained with this approach indicate that PCP is a possible public health hazard.

Animals↗

PubMed1992

Pharmacokinetic concepts in assessing intake of pentachlorophenol by rats after exposure through drinking water.

The objective of this study was to predict concentrations of a toxicant in plasma after exposure to the toxicant through drinking water using basic pharmacokinetic principles. As an example, we studied pentachlorophenol (PCP), a widely used wood preservative of public health concern as an environmental pollutant. We added PCP to the drinking water (30 micrograms/mL) of five rats for 3 days. Blood was sampled, and water consumption was monitored every 12 h on the days 1 and 2 and every 3 h on day 3. After a 4-day washout, a PCP dose of 2.5 mg/kg was given intravenously, and blood was withdrawn at selected times for 2 days. PCP concentrations in plasma were measured by capillary gas chromatography. A one-compartment model with zero-order input and kinetic parameters (clearance, volume of distribution, and bioavailability) estimated after intravenous administration adequately predicted PCP concentrations in plasma during exposure to PCP. The average steady-state concentration (Css), which reflects the overall exposure, was predicted using the clearance (CL) concept [i.e., Css = (bioavailability.rate of intake)/CL] and compared with the observed value. The data for PCP demonstrate the potential utility of CL and other kinetic concepts in assessing exposure to a toxicant in drinking water, food, or air.

Administration, Oral↗

PubMed1992

Styrene in adipose tissue of nonoccupationally exposed persons.

Given a styrene tissue/blood partition coefficient of ca. 39 and a relatively low perfusion rate of ca. 0.03 ml/min-g tissue, adipose tissue provides a useful physiologically damped integrative measure of environmental exposure. Styrene in the adipose tissue of nonoccupationally exposed individuals was measured for the first time. Tissue samples obtained from elective surgery patients and postmortem donors were analyzed by capillary gas chromatography and found to contain 1.12 +/- 1.06 (mean +/- SD) ppm styrene. Using these measured tissue levels and an apparent clearance of styrene (defined as the ratio of blood clearance to adipose tissue/blood partition coefficient), environmental intake of styrene was estimated to be 2.23 mg/hr, corresponding to an inhaled concentration of 1.96 mg/m3 (476 ppb). This value is two to three orders of magnitude higher than typical breathing zone air measurements, indicating additional undiscovered sources of styrene exposure.

Adipose Tissue↗

PubMed1992

Disposition, bioavailability, and serum protein binding of pentachlorophenol in the B6C3F1 mouse.

The toxicokinetics of pentachlorophenol (PCP) were studied in B6C3F1 mice, a strain in which PCP was previously found to be carcinogenic. In a crossover design, doses of 15 mg/kg were given intravenously (bolus) and orally (gastric intubation) to six animals. Concentrations of PCP in blood, urine, and feces were measured by capillary gas chromatography with electron-capture detection. After intravenous administration, the values of clearance and volume of distribution were 0.057 +/- 0.007 L/hr/kg and 0.43 +/- 0.06 L/kg, respectively. These two parameters exhibited low intermouse variability (coefficients of variation less than 14%). The elimination half-life was 5.2 +/- 0.6 hr. After oral administration, the PCP peak plasma concentration (28 +/- 7 micrograms/ml) occurred at 1.5 +/- 0.5 hr and absorption was complete (bioavailability = 1.06 +/- 0.09). The elimination half-life was 5.8 +/- 0.6 hr. Only 8% of the PCP dose was excreted unchanged by the kidney. PCP was primarily recovered in urine as conjugates. A portion of the dose was recovered in urine as the mutagen, tetrachlorohydroquinone (5%) (TCHQ), and its conjugates (15%). For both PCP and TCHQ, sulfates accounted for 90% or more of the total conjugates (glucuronides and sulfates).

Administration, Oral↗

PubMed1992

Assessment of pentachlorophenol exposure in humans using the clearance concept.

1. Pentachlorophenol (PeCP), a widely-used wood preservative, is a ubiquitous compound which has been found to be carcinogenic in mice. The objective of this study is to assess the average net daily intake of PeCP in cohorts of individuals who are: (1) not specifically exposed to PeCP, (2) residents of homes made of PeCP-treated logs and (3) occupationally exposed to PeCP. 2. The average net daily intake was calculated using a basic pharmacokinetic principle, the clearance (CL) concept: net daily intake equals CL (in 1 d-1) times the average steady-state concentration of PeCP in plasma (Css). Css values reported in the literature were used for the calculations. 3. Because the two definitive studies on PeCP toxicokinetics in humans have given conflicting results, kinetic information from human exposure to PeCP was reviewed. Plasma clearance was estimated from retrospective analysis of urine and plasma concentrations measured in people after long-term exposure to PeCP. An overall clearance of 0.425 l d-1 was obtained. 4. In groups of individuals who are not specifically exposed to PeCP, net daily intake estimated in eight countries varied from 5 micrograms (Nigeria) to 37 micrograms (The Netherlands). Net intake was between 51 micrograms d-1 and 157 micrograms d-1 in residents of homes made of PeCP-treated logs. In individuals occupationally exposed to PeCP, net daily intake varied widely (from 35 micrograms to about 24,000 micrograms) depending on the type of work.

Adult↗

PubMed1992

Transfer of autologous haemoglobin from the peritoneal cavity during peritoneal dialysis.

Transfer of autologous haemoglobin from the peritoneal cavity was evaluated retrospectively in 14 patients who received this marker intraperitoneally (group 1) during routine continuous ambulatory peritoneal dialysis (CAPD). Five additional patients were studied during acute peritonitis (group 2). A model for balance of both dialysate volume and amount of haemoglobin is developed to assess movement of the compound into lymph or adjacent tissues. Under the conditions of the study the transfer was slow (8 +/- 10 ml/h) in patients without peritonitis (group 1), and significantly faster (25 +/- 22 ml/h) in those with peritonitis (group 2). These clearance values are the upper limits for lymph flow.

Adult↗

PubMed1991

Theoretical model for both saturable rate and extent of absorption: simulations of cefatrizine data.

A pharmacokinetic model incorporating saturable rate of absorption of the Michaelis-Menten type was recently developed to fit cefatrizine (CFZ) plasma concentrations with time following oral administration of 500-mg capsules to humans. This model (MM) was statistically superior to models incorporating either first-order or zero-order absorption. However, the MM model does not predict the reduction in extent of absorption with dose observed in vivo. In this study, a model is proposed in which a time constraint, delta t, is added to the MM model. This new model (MM-delta t) is tested with data following doses of 250, 500, and 1000 mg of CFZ. When delta t is set to 1.5 hr, the predicted relative changes with dose in bioavailability, F, peak plasma concentration, Cmax, the time at which the peak concentration occurs tmax, and the mean absorption time, MAT, are generally in good agreement with the experimental data. The time interval of 1.5 hr is compatible with passage by a limited region within the small intestine where drug is absorbed by a facilitated transport mechanism. Influence of each absorption model parameter (Vmax, Km, and delta t) on total area under the concentration versus time curve (AUC), F, Cmax, and tmax, is assessed by simulation. The MM-delta t model is able to summarize the nonlinerity observed in both rate and extent of absorption.

Cefatrizine↗

PubMed1991

Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.

Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained beta-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, less than 1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.

Administration, Oral↗

PubMed1991

Relative anti-inflammatory effect of oral dexamethasone-beta-D-glucoside and dexamethasone in experimental inflammatory bowel disease in guinea-pigs.

The relative anti-inflammatory effect of dexamethasone and a prodrug, dexamethasone-beta-D-glucoside, has been assessed in guinea-pigs with experimentally-induced inflammatory bowel disease (IBD). The glucoside prodrug is designed to reach the large intestine following oral administration. The active agent is liberated when the prodrug is hydrolysed by glycosidases of colonic bacteria. Guinea-pigs were administered degraded carrageenan in their drinking water to produce experimental IBD. Starting on day 15, dexamethasone (1.3 mumol kg-1) or dexamethasone-beta-D-glucoside (1.3 or 0.65 mumol kg-1) was administered by gastric intubation once daily for 5 days. Relative to control animals, the drug and prodrug treatments significantly (P less than 0.05) reduced the total number of caecal ulcers. While there was no difference statistically between the drug and prodrug treatments, the data suggest that a lower dose of dexamethasone, administered as its glucoside prodrug, could reduce side-effects without reduced efficacy. These results support the hypothesis that localized delivery of dexamethasone to the large bowel can improve pharmacotherapy of IBD by reducing the side-effects associated with corticosteroids.

Animals↗

PubMed1991

Pentachlorophenol toxicokinetics after intravenous and oral administration to rat.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in rats. Doses of 2.5 mg/kg were given i.v. (bolus, five rats) and orally (gastric intubation, five rats). Concentrations in plasma, urine and faeces were measured by capillary g.l.c. with electron-capture detection. 2. After i.v. administration, the clearance and volume of distribution at steady state were 0.026 +/- 0.003 l/h per kg and 0.25 +/- 0.02 l/kg, respectively. These two parameters exhibit low inter-rat variability (coefficients of variation less than 15%). The half-life of the initial decline of PCP plasma concn. was less than 1.3 h, while the second phase half-life was 7.11 +/- 0.87 h. 3. After oral administration the peak plasma concn. (7.3 +/- 2.8 micrograms/ml) occurred between 1.5 and 2 h and absorption was complete (bioavailability = 0.91-0.97). No distinct distribution phase was observed and the elimination half-life was 7.54 +/- 0.44 h. 4. PCP clearance is essentially metabolic since only 5.3 +/- 0.2% dose is eliminated unchanged by the kidney. About 60% dose was recovered in urine, mainly as conjugated PCP and conjugated tetrachlorohydroquinone (TCHQ). 5. For both routes of administration, about 10% dose was recovered in faeces as PCP and/or metabolites, which indicates that biliary excretion contributes to total elimination.

Absorption↗

PubMed1990

Simultaneous assay of pentachlorophenol and its metabolite, tetrachlorohydroquinone, by gas chromatography without derivatization.

A sensitive capillary gas chromatographic method was developed for the simultaneous determination of pentachlorophenol and its major metabolite, tetrachlorohydroquinone, in plasma, urine and feces. The method involved a simple one-step liquid-liquid extraction with diethyl ether and electron-capture detection gas chromatography on a fused-silica capillary column coated with 50% methylsilicone-50% trifluoropropylsilicone. The detection limit of both compounds was 50 ng/ml in plasma (from an initial volume of 0.1 ml), 100 ng/ml in urine and 100 ng/g in feces. Optimal conditions for both chemical and enzymatic hydrolysis were defined to measure conjugates of both pentachlorophenol and tetrachlorohydroquinone in urine. Tetrachlorohydroquinone was found to be unstable in plasma and urine; means to prevent its degradation during sample collection and storage by addition of ascorbic acid and ethylenediaminetetracetic acid are presented. This chromatographic method was shown to be precise, accurate and specific. It was successfully applied to toxicokinetic studies in rat.

Animals↗

PubMed1990

Saturable rate of cefatrizine absorption after oral administration to humans.

This study examined the absorption kinetics of cefatrizine, an amino-beta-lactam antibiotic, after oral administration of a single 500-mg dose to 12 healthy volunteers. Plasma concentrations were determined by high performance liquid chromatography. The plots of the percentage of drug unabsorbed and the apparent rate of cefatrizine absorption as a function of time showed, first, a delay and, then, an almost constant rate of absorption with a tendency to move toward first-order kinetics at the end of the process. Three compartmental models incorporating a lag time and first-order elimination kinetics, but differing in their input rate, were used for analysis of the time course of cefatrizine plasma concentrations. The model with first-order absorption kinetics was clearly inadequate. The results were improved with the model for which the rate of absorption is constant, but a model incorporating saturable absorption kinetics of the Michaelis-Menten type improved the fit further. This last model was statistically superior to the constant-rate input model in 6 out of 12 subjects, according to the likelihood-ratio method. Because of the innovative feature of the model incorporating the Michaelis-Menten equation, simulations of the effect of altering the model parameters and the dose administered on the concentration-time profile, were performed. Different hypotheses which might explain why cefatrizine absorption kinetics fits the Michaelis-Menten equation were examined. The observation of saturable absorption kinetics is consistent with a carrier-mediated transport previously reported to occur in the gastrointestinal tract of rats.

Absorption↗