Pharmacokinetic and In Vitro Sensitivity Studies on Ampicillin and Congener Prodrugs in Equidae

Sarasola Salaberria, Patxi (1993) Pharmacokinetic and In Vitro Sensitivity Studies on Ampicillin and Congener Prodrugs in Equidae. PhD thesis, University of Glasgow.

Abstract

The present study was conducted to evaluate alternative methods to prolong the persistence of ampicillin in the horse. Artificial alkalinisation (pH > 7.91 +/- 0.13) and acidification (pH < 4.24 +/- 0.13) of equine urinary pH achieved by intragastric administration of sodium bicarbonate (100, 200, 300, and 400 [x3] mg/kg) over a six day period, and ammonium chloride (200, 300, and 400 [x3] mg/kg) over a five day period respectively, did not produce any significant changes in the plasma disposition of ampicillin when administered as an IV bolus (10 mg/kg) of the sodium salt to horses. These results were attributed to the lack of changes in the extent of reabsorption of ampicillin from the urine into plasma caused by the zwitterion characteristics of the antibiotic. However, the alkalinisation of urine appeared to affect the fraction of the dose of ampicillin recovered in the urine since only a small fraction could be measured, (<15 %) presumably resulting from a degradation of the antibiotic in the basic media. The plasma disposition of ampicillin was altered when probenecid, a competitor of the active tubular secretion of penicillins, was administered intragastrically to horses at a 75 mg/kg dose rate one hour prior to the administration of ampicillin IV. The presence of probenecid prolonged the elimination of ampicillin significantly (P< 0.05), as reflected in an almost twofold increase in the elimination half-life (t1/2? = 0.701 h vs t1/2?= 1.198 h) and mean residence time values (MRT = 48.32 min vs MRT = 95.37 min) of ampicillin when coadministered with probenecid. It was therefore concluded that administration of probenecid was a suitable method for prolonging the persistence of ampicillin in the horse. In addition, the presence of probenecid appeared to restrict the distribution of ampicillin as reflected in a significant reduction (P< 0.05) in the volume of distribution of the antibiotic at steady-state (Vdssobs = 207.17 +/- 20.89 ml/kg vs VdsSobs = 166.70 +/- 11.21 ml/kg). The short persistence of ampicillin in the horse was also overcome by the administration of the antibiotic as an IV infusion over a prolonged period. This novel method of administration of ampicillin in the horse, enabled accurate control on the amount of ampicillin delivered per unit of time and was shown to be suitable for those circumstances when a compromised vascular supply would impair the absorption of the antibiotic from the injection site when administered IM. Changes in the infusion rate delivered (Ro= 13.78, 19.34, and 23.48 mug/min/kg) correlated well (R=0.994) with the concentration of the antibiotic at steady-state (Cpss = 4.98, 6.37 and 8.25 fig/ml) and the AUC obtained (AUC = 27.83, 33.89 and 42.10 mug.h/ml) indicating the reliability of this method of administration. The slower absorption and elimination achieved following oral administration of drugs was investigated by the administration of bacampicillin, an ampicillin prodrug, in horses and ponies. Following intragastric administration of bacampicillin to horses and ponies, more than 40 % was absorbed from the gastrointestinal tract (F = 41.01%), and the concentrations achieved suggested that oral administration of bacampicillin hydrochloride at dose equimolar to 10 mg/kg of ampicillin sodium every 8 to 12 hours, would be suitable to treat infections caused by sensitive bacteria. In an attempt to slow the hydrolysis of bacampicillin into ampicillin and thus prolong the persistence of the antibiotic within the body, the esterase activity present in plasma and in red blood cells was artificially reduced. The oral administration of dichlorvos, an organophosphate anthelmintic, produced a depression of plasma and erythrocyte esterase activity greater than 95%, at the time of bacampicillin administration. However, the reduction of esterase activity did not have any influence on the absorption and pharmacokinetics of bacampicillin as no significant differences were found between the pharmacokinetic results obtained following administration of bacampicillin and those following the administration of bacampicillin and dichlorvos. It appeared therefore that the small residual esterase activity present in plasma and red blood ceils was sufficient to convert bacampicillin into ampicillin, or that other factors such as the plasma pH and the esterase activity present in other body tissues may have played a role in the results obtainned.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Quintin A McKellar
• Keywords: Veterinary science, Animal sciences, Pharmaceutical sciences
• Date of Award: 1993
• Depositing User: Enlighten Team
• Unique ID: glathesis:1993-75459
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 20:03
• Last Modified: 19 Nov 2019 20:03
• URI: https://theses.gla.ac.uk/id/eprint/75459