Search PubMed⌕ Search

Biomedical subjects

J T Slattery

Publications and source records attributed to J T Slattery.

At least 91 records · Page 5Linked to original sources
PubMed1985

Effect of halothane-oxygen anesthesia on the pharmacokinetics of diazepam and its metabolites in rats.

Inhalation anesthetics have been shown to substantially diminish the clearance of several drugs eliminated by hepatic routes. The purpose of the present study was to determine the influence of halothane-oxygen anesthesia on the hepatic metabolism of diazepam and its proximate metabolites in anesthetized rats whose physiologic status was monitored and maintained. The portal vein, femoral artery and bile duct of male Sprague-Dawley rats 370 to 395 g, were cannulated under pentobarbital anesthesia. After a 2-hr recovery period, [14C]diazepam was administered in to the portal vein as a 0.25-mg/kg bolus followed immediately by a 0.25-mg/kg/hr infusion by the same route. After the attainment of steady state, the halothane group (seven rats) received 1% halothane in oxygen whereas the control group (six rats) continued to breathe room air. The diazepam infusion was maintained for an additional 3 hr. Concentrations of diazepam, N-desmethyldiazepam, 4-hydroxyphenyldiazepam and 3-hydroxydiazepam were determined in plasma; these metabolites as well as oxazepam and N-desmethyl-4-hydroxyphenyldiazepam were also determined in bile. Radioactivity in bile was approximately 98% conjugated; radioactivity in plasma was approximately 30% conjugated. Halothane anesthesia caused an increase in the concentrations of diazepam and its metabolites in plasma, but the steady-state ratios of the concentration of the individual metabolites in plasma to diazepam concentration were not changed. The intrinsic clearance of diazepam was decreased by 42%, P less than .01, and the ratio of formation to elimination clearance of the metabolites measured in plasma was not changed. Halothane anesthesia also decreased the excretion rate of 14C into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1984

Persistence of antifolate activity in skin of rats following systemic administration of methotrexate.

Studies of the time course of methotrexate-derived antifolate activity (methotrexate activity) in plasma and skin of rats have been carried out to evaluate the hypothesis that the formation of therapeutically active poly-gamma-glutamyl conjugates of methotrexate in skin after systemic administration of the drug will result in the prolongation of methotrexate effects in skin. Such a finding may eventually bear on the use of the drug in the treatment of psoriasis. Three groups of 4 rats received a single i.v. dose of methotrexate, 5, 20, or 40 mg/kg, respectively. Serial skin and plasma samples were obtained over 48 h from each rat and analyzed for methotrexate activity by a dihydrofolate reductase enzyme inhibition assay. The values of pharmacokinetic parameters describing the disposition of the drug were calculated from plasma data using standard methods. Skin to plasma ratio of methotrexate activity was also calculated each time a skin sample was obtained. Pharmacokinetic parameter values and skin to plasma ratios were not significantly different between doses. Methotrexate activity declined biexponentially in plasma and skin. The terminal half-life in plasma (mean +/- SD) was 20.3 +/- 9.2 h. At early times, methotrexate activity in skin was less than plasma, but at later times activity in skin was an order of magnitude greater than that in plasma. In a preliminary study to determine whether the persistent activity in skin is associated with the presence of poly-gamma-glutamyl conjugates of methotrexate, a rat was dosed with tritiated methotrexate, 0.18 mg/kg, i.v., and skin was obtained 24 h later. Skin homogenate was treated with papain and applied to an anion-exchange column for cleanup prior to injection on a reversed-phase high-pressure liquid chromatography system. Methotrexate poly-gamma-glutamates were identified by elution with authentic standards and specific hydrolysis with carboxypeptidase G1.

Animals↗
PubMed1984

Pharmacokinetics of the poly-gamma-glutamyl metabolites of methotrexate in skin and other tissues of rats and hairless mice.

The time course of methotrexate (MTX) and its poly-gamma-glutamyl metabolites (PGGs) was examined in the skin, liver and blood of rats and full-thickness skin, epidermis and blood of hairless mice to determine their contribution to the persistence of antifolate activity after a single dose of MTX. [3H]MTX was administered i.v. to rats and i.p. to mice in a dose similar, on a microgram per kilogram basis, to that administered to humans for the treatment of psoriasis. The animals were sacrificed at various times after the dose and skin and other tissues were analyzed for the presence of MTX and the PGGs. The percentage of total antifolates in the skin of rats that was attributable to the PGGs was less than 30% at all times examined (6 to 72 hr). However, more than half of the PGGs present contained three or more glutamic acid residues. The skin from the hairless mice was separated into dermis and epidermis to determine if MTX and its metabolites were present in the ostensible site of action in psoriasis, the epidermis (separation of epidermis from dermis is prohibited by hair in the rat). The PGGs accounted for less than 13% of total antifolates in full-thickness skin of mice at all times studied. The epidermis contained more antifolates, on a picomole per gram basis, at all times (4 to 24 hr) than did the full-thickness skin. In the epidermis, the percentage of total antifolates contributed by the PGGs rose to 35% by 24 hr, more than twice its value at earlier times.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Caudal anesthesia with lidocaine or bupivacaine: plasma local anesthetic concentration and extent of sensory spread in old and young patients.

Continuous caudal peridural anesthesia with 2% lidocaine (6 mg/kg) or 0.75% bupivacaine (2.2 mg/kg), both with epinephrine 1:200,000, was studied in two groups of male patients, younger than 40 or older than 55 yr old, respectively. Patients receiving lidocaine in the younger group (n = 6) were 32 +/- 5.2 (mean +/- SD) yr old and weighed 75 +/- 12 kg, while those in the older group (n = 16) were 66 +/- 5.3 yr old and weighed 72 +/- 8.2 kg. Patients receiving bupivacaine in the respective groups were 27 +/- 7.0 yr old (n = 5), and 76 +/- 10 kg compared to 69 +/- 10 yr (n = 14) and 75 +/- 10 kg. Anesthesia was satisfactory in all patients. Extent of sensory anesthesia, peak plasma lidocaine or bupivacaine concentrations, and area under the plasma concentration-time curves were independent of age. No local anesthetic toxicity was observed and peak drug concentrations were below those commonly associated with toxicity.

Adult↗
PubMed1983

Maintenance-dose prediction based on a single determination of concentration: dose of parent drug required to give a desired steady-state concentration of metabolite.

A method for predicting the maintenance dose of parent drug required to give a desired steady-state concentration of metabolite, using a single determination of metabolite concentration in serum following the first dose of parent drug, is described. Clinical evidence that such a method is feasible for the drug-metabolite pair imipramine-desipramine has been reported. The error inherent in an estimation of maintenance dose based on a single determination of metabolite concentration is a function of sampling time and the first-order elimination rate constants for parent drug and metabolite (K and km, respectively). The method is applicable to drug-metabolite pairs in general by selecting the sampling time (t*) to give minimum error: t* equal 1/km + 1.3/K, when km less than or equal to K, and t* equal 1/K + 1.3/km, when km greater than K (bars denote population mean value). The error expected to be encountered in the application of the method to specific drug-metabolite pairs can be analyzed by the graphical methods described.

Chemistry, Pharmaceutical↗
PubMed1983

Maintenance-dose prediction based on a single determination of concentration: general applicability to two-compartment drugs with reference to lithium.

A general approach to the selection of the maintenance dose (Dm) required to give a desired steady-state concentration of drug based on a single determination of concentration after a test dose (C*) is extended to drugs with two-compartment pharmacokinetic characteristics. Using the equation developed, the value of the proportionality factor relating 1/Dm to C was found to be within 3.2% of the value calculated from a published nomogram for lithium. The inherent error is shown to be a function of the value of the hybrid rate constants alpha and beta, as well as the value of an intercompartmental transfer rate constant, k21, in an individual.

Humans↗
PubMed1983

Effect of liposome dose on the elimination of small unilamellar sphingomyelin/cholesterol vesicles from the circulation.

The effect of the liposome dose of bovine brain sphingomyelin/cholesterol (2/1; mol/mol) small unilamellar vesicles (mean diameter 187 42A) on the rate of elimination of the vesicles from the circulation of mice was investigated. The results of the study indicated that the relative rate of elimination of the vesicles from the blood depended on the amount of intravenously administered liposomal lipid. The distribution of the liposomes in vivo was followed by monitoring entrapped In-111. In all tissues examined, the uptake of the liposomes was a dose-dependent process. An examination of the dose dependency of the distribution of the administered liposomes in the blood and liver at 23 hours post-injection, and of the kinetics of the elimination of these vesicles from the blood, suggests a hepatic uptake process involving two parallel pathways. One pathway is apparently a capacity-limited Michaelis-Menten process; the other pathway is a linear, non-saturable process. These pathways operate in parallel but respectively dominate at the low end and the high end of the dose range examined.

Animals↗
PubMed1982

Analysis of acetaminophen metabolites in urine by high-performance liquid chromatography with UV and amperometric detection.

Acetaminophen and several of its metabolites are separated isocratically on a reversed-phase (C18) column using a mobile phase of 7% methanol and 0.75% glacial acetic acid in 0.1 M KH2PO4. Metabolites that can be separated include the sulfate, glucuronide, cysteine, and mercapturic acid conjugates of acetaminophen, as well as 3-hydroxyacetaminophen, 3-methoxyacetaminophen, and 3-methylthioacetaminophen. Although all of the metabolites can be detected by UV spectrophotometry, the sensitivity limits of detection are improved significantly for acetaminophen and all of the metabolites except the sulfate and glucuronide, by amperometric detection (electrochemical) of the same sample as it elutes from the UV detector. Minimal detectable limits (signal-to-noise ratio greater than or equal to 2) for acetaminophen and its metabolites, other than the glucuronide and sulfate conjugates, were in the order of 1--2 ng injected on column using UV detection at 248 nm, and 0.1--0.5 ng using electrochemical detection at + 0.60 V with reference to an Ag/AgCl standard electrode.

Acetaminophen↗
PubMed1981

Acetaminophen pharmacokinetics after overdose.

Concentrations of acetaminophen in serum and urinary excretion rates of acetaminophen glucuronide and acetaminophen sulfate were determined in a 15-year-old female who had ingested an overdose which resulted in the absorption of an estimated 9.92 g of acetaminophen. The results obtained are in reasonably good agreement with predictions of acetaminophen disposition based upon a previously developed pharmacokinetic model of capacity-limited acetaminophen elimination, but additional studies are needed to refine that model.

Acetaminophen↗
PubMed1980

Comparative pharmacokinetics of coumarin anticoagulants. XLVI: Effect of treatment of phenobarbital on pharmacokinetics of (S)-(-)-warfarin in rats.

This investigation was carried out (a) to determine if the enzyme inductive effect produced by phenobarbital reduces the interindividual variability in the biotransformation of a drug, as suggested in the literature; (b) to test whether the intrinsic clearance of free drug, for drugs exhibiting restrictive clearance, reflects the activity of drug-metabolizing enzyme systems; and (c) to determine if enzyme induction affects the apparent volume of distribution of a drug that tends to concentrate in the liver. Twelve pairs of adult male rats, matched with respect to their serum warfarin free fraction, received an intravenous injection of (S)-(-)-warfarin, 0.6 mg/kg, after four daily injections of either saline solution or phenobarbital (75 mg/kg). Phenobarbital treatment increased both the total and intrinsic clearance of (S)-(-)-warfarin almost threefold but did not reduce the coefficient of variation of the intrinsic clearance. Serum protein binding of (S)-(-)-warfarin was not affected by phenobarbital treatment. The biological half-life of warfarin and the duration of its anticoagulant effect were reduced substantially by treatment with phenobarbital. Consistent with pharmacokinetic theory, the relationship between total clearance and the free fraction of warfarin in serum remained approximately linear, but the slope of the regression line was increased for the animals treated with phenobarbital.

Animals↗
PubMed1980

A pharmacokinetic model-independent approach for estimating dose required to give desired steady-state trough concentrations of drug in plasma.

A maintenance dose designed to give a desired minimum concentration of drug in plasma at steady-state can be determined in a model-independent manner assuming that concentration-time data needed for the calculation are obtained after absorption and distribution are complete. Using a few concentration-time points obtained after the first dose, numerical values of beta and Z a parameter consisting of different pharmacokinetic parameters for different models, can be obtained. An administration interval (tau) can be chosen based on beta. Using the values of beta, Z, and tau, a maintenance dose is calculated. This approach will allow calculation of a maintenance dose when drug is present in plasma at the time the first monitored dose is given.

Humans↗
PubMed1980

Protein binding of several drugs in serum and plasma of healthy subjects.

The protein binding of phenytoin, propranolol, salicylic acid, warfarin, and bilirubin was determined in heparinized plasma and serum obtained from the same healthy adult subjects. There were no significant differences in the free fraction values of these compounds in plasma and serum. Addition of heparin to serum had no significant effect on protein binding. Contact with Vacutainer stoppers increased the free fraction of the weak base propranolol in serum and plasma but no significant effect on the protein binding of the other, weakly acidic compounds tested. The lack of differences in the protein binding of phenytoin, salicylic acid, warfarin, and bilirubin in human plasma and serum is in contrast with the pronounced differences observed previously in rat serum and plasma.

Adult↗
PubMed1979

Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin.

The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.

Adult↗
PubMed1979

Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin.

The purpose of this investigation was to determine whether the anti-inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.

Adult↗
PubMed1979

Acetaminophen kinetics in acutely poisoned patients.

A kinetic model of acetaminophen elimination over a wide dose range has been developed on the basis of (1) kinetic data from normal adults who received a usual dose (up to 2 gm) of the drug and (2) the composition of urinary metabolites of acetaminophen excreted within 24 hr by 29 patients who had ingested up to 26 gm of acetaminophen in suicide attempts (including 2 that were fatal and 5 with evidence of severe intoxication). The model consists of the following parallel pathways: conjugation with glucuronide by Michaelis-Menten kinetics, conjugation with sulfate by Michaelis-Menten kinetics, renal excretion of acetaminophen by apparent first-order kinetics, and formation of an oxidative metabolite (which is responsible for the hepatotoxicity of acetaminophen) by apparent first-order kinetics. There is good agreement between the model-predicted and actual urinary excretion of individual acetaminophen metabolites for doses of 0.8 to 26 gm and between model-predicted and actual plasma acetaminophen concentrations in both the low (normal subjects) and high (intoxicated subjects) concentration ranges. Computer simulations indicate that unsaturation of acetaminophen sulfate formation, previously shown to be feasible in vivo, should decrease the formation of the hepatotoxic metabolite. This prediction is consistent with experimental data obtained in preliminary studies on mice.

Acetaminophen↗