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Biomedical subjects

T N Tozer

Publications and source records attributed to T N Tozer.

At least 55 records · Page 3Linked to original sources
PubMed1987

Concurrent intravenous administration of a labeled tracer to determine the oral bioavailability of a drug exhibiting Michaelis-Menten metabolism.

The theoretical accuracy of concurrent administration of labeled intravenous tracer and oral doses to estimate the bioavailability of drugs exhibiting Michaelis-Menten kinetics was determined by computer simulation. The simulation model consisted of sampling and hepatic compartments with elimination occurring by hepatic metabolism according to the venous equilibration model. The relationships between error in bioavailability estimation and dose, metabolic activity (Vmax), first-order absorption rate constant (ka), and volume of distribution (V) and the fraction of the dose absorbed were examined. Error was hypothesized to be relatively low when conditions result in a relatively constant value of clearance after oral dosing or when the concentration-time curves after intravenous and oral dosing are similar. The results were consistent with these hypotheses and, under most conditions, error was less than 15%. The effects, on error, of altering the intravenous tracer dose input and having a lag time in absorption of drug from the oral dose were also determined. In general, accuracy was improved by delaying administration of the iv tracer for a time equal to 50% of the oral dose peak time or by administering the tracer dose by constant-rate infusion from the time of oral dosing to the peak time. Lag time in absorption of the oral dose was shown to often result in overestimates in bioavailability of greater than 50%.

Administration, Oral↗
PubMed1986

Human erythrocyte membrane permeability and nitroxyl spin-label reduction.

Nitroxyl spin labels are paramagnetic compounds that have demonstrated utility as contrast enhancing agents in proton magnetic resonance imaging. The time-course of contrast enhancement depends on distribution and elimination of these agents. Reduction, resulting in formation of the diamagnetic hydroxylamine, is the major metabolic pathway observed in vivo. This bioreduction has implications for the design of contrast agents and for understanding their imaging behavior. Bioreduction has been shown to occur, at least in part, intracellularly. As such, cell membrane permeability to nitroxyl spin labels may influence their bioreduction. In this study, this influence was examined using eight nitroxyl derivatives and the human erythrocyte suspension as a model biomembrane system. Ionizable weak acids and bases were found to equilibrate rapidly across the erythrocyte membrane with half-times of equilibration ranging from less than 10 s to 1.6 min. These derivatives had low octanol:buffer distribution coefficients and were extensively ionized at the pH of the system (7.0). A strong acid, a phosphate ester, and a quaternary amine derivative were excluded by the cell membrane. Reduction of nitroxyl spin labels by the erythrocyte was shown to occur intracellularly. Except for the impermeable probes, the reduction rate was slow in comparison with the membrane penetration rate. The structural dependence of reduction rate was unrelated to penetration rate but correlated well with that observed in other reducing systems, namely, ascorbic acid solution and rat tissue homogenates.

Buffers↗
PubMed1986

Hepatic binding and Michaelis-Menten metabolism of drugs.

Certain drugs with metabolism that obeys Michaelis-Menten kinetics are extensively bound in the liver. During the initial distribution phase after a single dose, the binding sites act as a "sink" and compete with the metabolizing enzymes for the drug. After this phase is completed, the bound sites act as a source of drug for the enzymes. Computer simulations of a perfused liver system, with well-stirred reservoir and hepatic compartments, were performed to assess whether or not such binding, as measured by the partition coefficient (Kp) between the liver and the emergent venous blood, affects the tendency to saturate metabolism. Metabolism was assumed to follow Michaelis-Menten kinetics and only unbound drug was assumed to have access to the enzymes. The value of Kp was varied to determine the effect of binding (instantaneous equilibrium) on the tendency to saturate metabolism. The effect of binding rate was also determined by adjusting the association and dissociation rate constants while maintaining a constant value of the equilibrium partition coefficient. Input into reservoir and liver were done to simulate "intravenous" and "oral" dosing, respectively. The average clearance (dose divided by the area under the reservoir concentration-time curve) of the "intravenous" dose increased and the bioavailability of the "oral" dose decreased when the value of Kp was increased, indicating that the tendency to saturate metabolism was reduced by hepatic binding. This effect diminished as the binding rate constants were made smaller, but was still substantial, when association was slower than metabolism.

Administration, Oral↗
PubMed1986

Extrahepatic extraction of salicylamide in dogs.

Extrahepatic conjugation may be an important mechanism for the metabolism of many phenolic compounds. We have observed dose-dependent sulfoconjugation of salicylamide (SAM) in the lung, kidney and forelimb of dogs during steady-state infusions. The lungs alone accounted for more than one-half the total elimination at the lowest infusion rate (0.3 microgram/min/kg). The limbs appeared to play an important secondary role in SAM elimination whereas the kidneys made only a minor contribution to total elimination. At the highest infusion rate (500 micrograms/min/kg), extrahepatic extraction approached zero and elimination by the three extrahepatic sites fell to less than 31% of total elimination. Dose-dependent elimination at the three extrahepatic sites was responsible for most of the dose dependence observed in these studies. Extrahepatic extraction was insensitive to plasma inorganic sulfate. Clearance significantly, but only slightly, increased on coinfusing sodium sulfate at a rate that increased plasma inorganic sulfate from one-sixth (after depletion by SAM infusion) to two times normal.

Animals↗
PubMed1985

Factors affecting nitroxide reduction in ascorbate solution and tissue homogenates.

Because of their paramagnetic properties, nitroxides are potentially useful as contrast agents in magnetic resonance imaging (MRI). They are reduced in vivo to their corresponding hydroxylamines which are nonparamagnetic and have no contrast enhancing property. Nitroxides with high resistance to reduction would be advantageous as pharmaceutical contrast enhancing agents. We show that in the presence of ascorbic acid and in tissue homogenates, the reduction is faster for piperidine than for pyrrolidine nitroxides and for positively-charged than for negatively-charged derivatives. The data also suggest that nitroxide reduction in tissue homogenates is mainly due to sulfhydryl groups on proteins and that endogenous ascorbic acid plays a relatively minor role.

Animals↗
PubMed1985

Enhanced MRI of tumors utilizing a new nitroxyl spin label contrast agent.

Nitroxyl spin labels have been shown to be effective in vivo contrast agents for magnetic resonance imaging (MRI) of the central nervous system, myocardium, and urinary tract. A new pyrrolidine nitroxyl contrast agent (PCA) with better resistance to in vivo metabolic inactivation than previously tested agents was studied for its potential to enhance subcutaneous neoplasms in an animal model. Twenty-two contrast enhancement trials were performed on a total of 15 animals 4-6 weeks after implantation with human renal adenocarcinoma. Spin echo imaging was performed using a .35 T animal imager before and after intravenous administration of PCA in doses ranging from 0.5 to 3mM/kg. The intensity of tumor tissue in the images increased an average of 35% in animals receiving a dose of 3 mM/kg. The average enhancement with smaller doses was proportionately less. Tumor intensity reached a maximum within 15 min of injection. The average intensity difference between tumor and adjacent skeletal muscle more than doubled following administration of 3 mM/kg of PCA. Well-perfused tumor tissue was more intensely enhanced than adjacent poorly perfused and necrotic tissue.

Animals↗
PubMed1985

Dose-dependent sulfoconjugation of salicylamide in dogs: effect of sulfate depletion or administration.

The effects of plasma inorganic sulfate concentrations on the dose-dependent kinetics of salicylamide (SAM) were examined in the dog. Decreasing plasma sulfate concentrations from 0.9 mM to less than 0.3 mM significantly decreased clearance of a small dose of SAM (5 mg/kg) to the sulfate conjugate. Infusing sodium sulfate to prevent the decrease in plasma inorganic sulfate concentration that follows a p.o. 20-mg/kg dose of SAM did not increase SAM elimination. However, sodium sulfate given p.o. decreased SAM bioavailability, which suggests a local effect of sulfate on intestinal first-pass metabolism of SAM. These data show some dependence of SAM metabolism on plasma inorganic sulfate concentrations, but only when they are markedly reduced.

Animals↗
PubMed1984

Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, alpha-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo, the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

Animals↗
PubMed1984

Theoretical considerations in the calculation of bioavailability of drugs exhibiting Michaelis-Menten elimination kinetics.

Two approaches used for bioavailability determination of drugs with Michaelis-Menten elimination kinetics were examined by computer simulation. The first method involved treating the drug as though its clearance remained constant during elimination, and the conventional method of taking the ratio of areas under the curve resulting from the oral and intravenous doses was used to calculate bioavailability. The second approach involved using the Michaelis parameters, Vmax and Km, to determine concentration dependent clearance values, but based these calculations on peripheral drug concentrations rather than on concentrations entering or in the liver. We have developed a simulation method that was used to test the accuracy of the above two methods. In the simulations described, Vmax, Km, and hepatic blood flow were chosen to represent a drug with an extraction ratio of 0.9 under linear conditions, but with Michaelis-Menten kinetics occurring at the doses given. Absorption was assumed to be first-order, and metabolism was assumed to occur only in the liver. These simulations showed that the most accurate determination of bioavailability requires knowledge of the direct contribution of oral absorption to the concentration of drug entering the liver. Unexpectedly, the results also showed that if a drug has a large volume of distribution or a large absorption rate constant, or both, use of the much simpler conventional method of bioavailability determination may be appropriate even in cases where the degree of saturation is substantial.

Absorption↗
PubMed1984

Renal function and therapeutic concentrations of phenytoin.

The plasma protein binding of phenytoin was studied in 40 adult patients with varying degrees of renal function impairment. The patients had stable renal function and no other condition known to alter phenytoin binding. Binding was measured by equilibrium dialysis, and the apparent affinity constant was calculated using the binding data and the measured serum albumin concentration. The apparent affinity of the drug decreased with a decrease in renal function. The decrease was most apparent in patients with creatinine clearances below 25 ml/min. The importance of altered binding on the therapeutic range is discussed, and a method of calculating equivalent therapeutic phenytoin concentrations from serum albumin and renal function is described.

Adult↗
PubMed1984

Dose-dependent bioavailability and metabolism of salicylamide in dogs.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in six dogs. Four minutes after each oral dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.60 +/- 0.11 liters/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Measurement of SAM clearance to individual metabolites indicated that the sulfoconjugation and not the glucuronidation pathway was responsible for the dose-dependent effects observed. These effects occurred even at doses not expected to have caused significant depletion of body stores of inorganic sulfate; the plasma concentration of inorganic sulfate decreased by only a maximum of 13 and 26% after the 5- and 10-mg/kg SAM doses, respectively. When [14C]SAM was given alone in tracer amounts, clearance values greatly exceeded cardiac output. This suggests that SAM undergoes sulfation in organs other than the liver and intestinal wall.

Animals↗
PubMed1983

Dependence of renal clearance on urine flow: a mathematical model and its application.

A mathematical model is developed to explain the dependence of renal clearance on urine flow rate. The model is tested using human data from the literature on compounds that are neither secreted nor reabsorbed by active or pH-sensitive mechanisms. The physiologically derived model explains and predicts the relationship between renal clearance and urine flow for a broad spectrum of compounds (i.e., butabarbital, chloramphenicol, creatinine, ethanol, theophylline, and urea) for which appropriate data are available.

Absorption↗
PubMed1983

Volume shifts and protein binding estimates using equilibrium dialysis: application to prednisolone binding in humans.

Sizable volume shifts can occur during equilibrium dialysis. This net movement of water, presumably caused by the osmotic effect of plasma proteins, reduces the concentration of binding proteins. In this paper the theory of protein binding estimation is extended, equations are developed for calculating the unbound and bound drug concentrations at dialysis equilibrium by correcting for the dilution of the proteins, and the equations are applied to a study of prednisolone. To demonstrate the importance of correcting for the volume shift, the parameters of a model in which prednisolone binds to corticosteroid-binding globulin, a protein with a limited capacity, and albumin were estimated. Unbound and bound concentrations were determined by correcting for both volume shifts (average 31%) and loss of drug to the buffer side, by correcting only for loss of drug to buffer side, and by making no correction at all (the usual method of treating equilibrium dialysis data). The error introduced by neglecting volume shifts was analyzed by comparing the parameter values obtained using the three methods. The results confirm the need to adjust for volume shifts and imply that reported binding constants obtained by equilibrium dialysis may be in error for many substances.

Blood Proteins↗
PubMed1983

Work in progress: nuclear magnetic resonance study of a paramagnetic nitroxide contrast agent for enhancement of renal structures in experimental animals.

A piperidinyl nitroxide stable free radical derivative, TES, was tested as an NMR contrast enhancer of renal structures in normal animals and animals with experimentally induced unilateral renal ischemia, renal vascular congestion, and hydronephrosis. Physiologic measurements indicated that TES is rapidly excreted in the urine with a clearance rate equal to the glomerular filtration rate. Because the compound is strongly paramagnetic, it increases the observable NMR intensity within the kidneys and urine in relatively low doses (0.04 to 0.9 g/kg). TES-enhanced spin echo renal images clearly demonstrated the presence of disease and functional abnormalities in diseased kidneys. These abnormalities were either not evident or only indirectly suggested on nonenhanced NMR images.

Animals↗
PubMed1983

Brain nuclear magnetic resonance imaging enhanced by a paramagnetic nitroxide contrast agent: preliminary report.

Contrast-enhancing agents for demonstrating abnormalities of the blood-brain barrier may extend the diagnostic utility of proton nuclear magnetic resonance (NMR) imaging. "TES," a nitroxide stable free radical derivative, was tested as a central nervous system contrast enhancer in dogs with experimentally induced unilateral cerebritis or radiation cerebral damage. After intravenous injection of TES, the normal brain showed no change in NMR appearance, but areas of disease demonstrated a dramatic increase (up to 45%) in spin-echo intensity and a decrease in T1 relaxation times. The areas of disease defined by TES enhancement were either not evident on the nonenhanced NMR images or were better defined after contrast administration. In-depth tests of toxicity, stability, and metabolism of this promising NMR contrast agent are now in progress.

Animals↗