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Biomedical subjects

T N Tozer

Publications and source records attributed to T N Tozer.

At least 73 records · Page 4Linked to original sources
PubMed1982

Urine flow-dependence of theophylline renal clearance in man.

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was administered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.

Adult↗
PubMed1980

Influence of renal failure on the hepatic clearance of bufuralol in man.

The beta-blocking agent bufuralol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (1'-hydroxy-bufuralol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behavior of the parent compound and three of its metabolites was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Bufuralol was given orally to all subjects (20 mg); some of the healthy volunteers also received the drug intravenously (5 mg). Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its halflife of elimination was not markedly influenced. The behavior of 1'-hydroxy-bufuralol was consistent with a decreased renal clearance. The behavior of bufuralol in patients with renal failure was analyzed using the clearance approach. From this analysis it appears that the presystemic biotransformation of bufuralol is decreased in renal failure and that changes in systemic clearance are compensated in our patients by modifications of the volume of distribution, resulting in little net change in the halflife of elimination.

Adrenergic beta-Antagonists↗
PubMed1980

Effect of saturable binding on the pharmacokinetics of drugs: a simulation.

The time-courses of both total and unbound drug concentrations with time were simulated under conditions of saturable binding to either plasma proteins or tissues, or both, following a single intravenous dose. The curves were either linear, convex, or concave, depending upon the extent of distribution and the intrinsic ability of an eliminating organ to remove drug from the body. Saturable binding should therefore be considered whenever data showing nonlinear semilogarithmic decline are to be interpreted.

Blood Proteins↗
PubMed1980

[Clearance concept applied to pharmacokinetics: 1. Application for the study of tolamolol (beta-blocking agent) in healthy volunteers (author's transl)].

Pharmacokinetics is often performed using models derived from the properties of exponential equations in order to analyse the behaviour of drugs in normal and pathological situations. A new approach based on the clearance concept allows an interpretation of the experimental data with models incorporating some physiological parameters, such as hepatic blood flow. The present study shows how the clearance concept may be used for the treatment of the results obtained in healthy volunteers. In particular, it allows an estimation of the importance of hepatic first-pass metabolism and validates the model used for the analyses of the kinetics of tolamolol.

Humans↗
PubMed1979

Salicylate clearance, the resultant of protein binding and metabolism.

Steady-state plasma salicylate concentrations and protein binding were examined in 9 normal subjects to determine relationships among daily dose, total and unbound salicylate concentrations, and total and unbound clearances. Aspirin doses ranging from 0.66 to 4.0 mg/kg/hr were given to steady state. Free and total salicylate concentrations were measured with spectrophotometric, fluorimetric, and equilibrium dialysis techniques. Although unbound clearance decreased over the therapeutic range, total clearance was unchanged. The former is a consequence of saturable metabolism; the latter, of saturable plasma protein binding as well as saturable metabolism. The fraction unbound increased linearly with unbound concentration. Clearance determined at 1.8 mg/kg/hr was used to predict levels obtained at higher aspirin doses. Analysis of residuals was used to ascertain the accuracy of the prediction. The coefficient of variation from prediction among subjects was found to be +/- 14%. It is concluded that, in normal subjects, salicylate clearance changes relatively little over the therapeutic range because the increasing fraction unbound compensates for decreasing clearance of unbound drug.

Adult↗
PubMed1977

Removal of phenytoin by hemodialysis in uremic patients.

The removal of phenytoin by hemodialysis was determined in seven uremic patients. Four patients were receiving phenytoin sodium for therapeutic purposes; three received one dose each intravenously to quantitate its disposition in uremia. The drug was measured in whole blood, plasma, saliva, and dialysate. Only 2% to 4% of the intravenous dose was recovered in the dialysate. Phenytoin clearance by dialysis was 7 to 14 ml/min; plasma clearance was 53 to 133 ml/min. Since hemodialysis contributes little toward shortening to 11-to-18-hour half-life of phenytoin in the uremic patients, no supplemental dose is necessary for uremic patients undergoing hemodialysis.

Adolescent↗
PubMed1976

Biliary secretion of methotrexate in rats and its inhibition by probenecid.

The biliary secretion of methotrexate was investigated in rats under steady-state conditions. The transport system involved was saturable and displayed Michaelis-Menten-type kinetics. Values for the maximal rate of transport and a transport constant analogous to the Michaelis constant were 12 mg/hr and 32 mg/liter (7 x 10-5 M), respectively. The inhibition of this transport mechanism by probenecid also was investigated, and the relationship between the plasma concentration of probenecid and the biliary clearance of methotrexate was elucidated. The value of Ki, the dissociation constant for the transport carrier-inhibitor complex, was 23 mug/ml (8 x10-5 M).

Animals↗
PubMed1976

Erythromycin.

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Biological Availability↗
PubMed1975

Hemodialysis of phenytoin in a uremic patient.

Removal of phenytoin by hemodialysis was determined in a uremic patient. The rate of appearance of the drug in dialysate, the plasma concentration with time, and the plasma clearance by dialysis were measured. Plasma protein binding of phenytoin was also determined. In spite of greatly reduced plasma protein binding in the uremic patient, removal rate was observed to be less than 10% of the rate of presentation of the dialyzer. During the 6-hr period of dialysis, the plasma concentration showed little change. The amount collected in the dialyase, 43.6 mg, was only a small fraction of drug in the body. These results indicate that replacement of phenytoin based on the amount of drug removed by dialysis is unnecessary in chronically dialyzed uremic patients. In addition, the utility of hemodialysis in phenytoin overdose is questioned.

Adult↗
PubMed1975

Nonliner tissue disposition: salicylic acid in rat brain.

A model was developed to detect nonlinear disposition of a drug in a tissue. The model was experimentally tested relating to salicylic acid disposition in the brain. Experimental data obtained in rats are reported for doses of 25 and 40 mg/kg ip. The parameters measured for each dose were the ratio of the area under the brain concentration-time curve to the area under the plasma concentration-time curve and the ratio of the maximum brain concentration of salicylic acid to the plasma concentration at that point in time. The ratios increased with dose; furthermore, ratios calculated using plasma concentrations corrected for plasma protein binding were dose dependent. Calculations performed on literature data for salicylic acid disposition in mouse brain corroborated the results of this sutdy. The existence of a saturable transport system for the elimination of salicylic acid from the brain is supported by the data presented. The rationale necessary to apply the model to any tissue is discussed.

Animals↗