An Investigation of the Kinetics of Co-trifamole, Co-trimoxazole, Trimethoprim Alone and Clavulanate Potentiated Ticarcillin with Consideration of the Prediction of Plasma Drug Concentration

Watson, Ian D (1985) An Investigation of the Kinetics of Co-trifamole, Co-trimoxazole, Trimethoprim Alone and Clavulanate Potentiated Ticarcillin with Consideration of the Prediction of Plasma Drug Concentration. PhD thesis, University of Glasgow.

Abstract

This thesis has examined aspects of the pharmcokinetics and assay of some antimicrobial chemotherapeutic agents with particular reference to the kinetics of fixed dose combinations and methods of predicting plasma concentration. An extracted diazotisation procedure for the assay of sulphonamides was evaluated and found to be satisfactory for estimation of both serum and urine concentrations. An analytical procedure was devised for the liquid chromatographic determination of trimethoprim and was used to conduct pharmacokinetic studies of trimethoprim in serum, urine, saliva and sputum. The disposition of trimethoprim and sulphonamide following the use of the fixed dose trimethoprim / sulphonamide combinations co-trimoxazole and co-trifamole were determined; the kinetics of sulphamethoxazole and sulphamoxole, the constituent sulphonamides, and trimethoprim were compared; for sulphamoxole this was the first full charaterisation of its kinetics. From the ratios of trimethoprim to either of the sulphomamides it was evident that the ratios achieved in urine were notably inferior to those found in vitro to have synergistic effect. Interpolation of these results with the clinical, bacteriological and pharmacokinetic findings of other workers strongly suggested that trimethoprim alone should be an effective treatment in uncomplicated urinary tract infection. A comparison of two trimethoprim formulations with different dosing schedules showed equivalent bioavailability and urine trimethoprim levels likely to be effective against susceptible organisms. A relationship between urinary trimethoprim concentrations and urine pH was noted. However serum concentrations were found to fall below the minimum inhibitory concentrations when the dosage schedule for 300 mg trimethoprim once daily was used; the 200 mg twice daily regimen was found to give rise to more acceptable plasma concentrations. Saliva concentrations of trimethoprim were obtained simultaneously with serum concentrations to allow consideration of the relationship between drug concentrations in these fluids for a drug which is highly ionized at physiological serum and saliva pH. Trimethoprim was an ideal probe for such an investigation, association between saliva and serum concentrations was established and there was a non-linear correlation between saliva flow rate and hydrogen-ion concentration. The prediction of serum trimethoprim concentrations from saliva concentration read from the regression line with observed serum concentration, was compared with a predictive equation based upon the Henderson-Hasselbalch equation and was found to be superior. In a double blind trial of trimethoprim and ampicillin in a general practice study of treatment of exacerbations of chronic bronchitis, the levels of trimethoprim in sputum were compared with clinical and bacteriological cure. There was no clear relationship but sputum trimethoprim levels well in excess of the minimum inhibitory concentration of sensitive organisms were shown to be acheived. The study demonstrated that trimethoprim was as effective as ampicillin in the treatment of exacerbations of chronic bronchitis. A further examination of prediction of serum trimethoprim concentration, using the data from the bioequivalence study was undertaken, using a computer programme, OPT. The programme uses Bayesian forecasting with estimates of maximum likelihood. The precision and bias of forecasts of future serum concentration were acceptable provided care was exercised in interpretation this would require a user having an appreciation of kinetic principles. Liquid chromatographic assays were developed for the determination of clavulanic acid and the isomers of ticarcillin in serum and urine. These assays were applied to the investigation of the kinetics of the combination of these drugs in subjects with various degrees of renal failure and undergiong dialysis. Both drugs showed notable renal clearance and their serum clearances decreased with increasing renal impairment, however the clearance of clavulanic acid in anephric subjects was greater than anticipated and it is postulated that this may be due to induction of metabolism. Haemodialysis cleared both drugs more efficiently than continuous ambulatory peritoneal dialysis, the former was associated with significant rebound levels of ticarcillin on cessation of dialysis. From the observed kinetics a dosing scheme for the administration of the ticarcillin/clavulanic acid combination was proposed. The limitations of current pharmacokinetic models and investigations are discussed and the relationship between antimicrobial and antineoplastic chemotherapy considered. It is anticipated that intracellular aspects of chemotherapy may be usefully examined.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Pharmacology
• Date of Award: 1985
• Depositing User: Enlighten Team
• Unique ID: glathesis:1985-76545
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 14:11
• Last Modified: 19 Nov 2019 14:11
• URI: https://theses.gla.ac.uk/id/eprint/76545