Stereoselective disposition of sulbenicillin in humans.

Stereoselective disposition of sulbenicillin (SBPC) epimers in healthy human volunteers was studied in order to clarify the differences in pharmacokinetic behavior between the epimers. Stereospecific high-performance liquid chromatography was used for the determination of SBPC epimers. Plasma protein binding was measured in vitro with an ultrafiltration method. The binding was stereoselective, with the unbound fraction (fu) of the R-epimer being approximately 1.3-fold greater than that of the S-epimer. SBPC was administered intravenously to human volunteers, and concentrations of SBPC in plasma and urinary excretion rates were measured. Renal clearance (CLR) for the unbound drug (approximately 400 ml/min) was greater than the glomerular filtration rate (GFR) (approximately 109 ml/min) for both epimers, suggesting that both epimers are secreted at the renal tubules. Renal tubular secretion appeared to be greater for the S-epimer. When probenecid was coadministered, the CLR values of both epimers were significantly reduced and were approximately equal to the GFR values. CLR was greater for the S-epimer (37.5 and 49.8 ml/min for R-SBPC and S-SBPC, respectively), which was simply due to the greater fu of the S-epimer in plasma. In contrast, total body clearance was greater for the R-epimer (67.8 and 56.3 ml/min for R-SBPC and S-SBPC, respectively) because of the stereoselective degradation of the R-epimer in plasma. It was revealed that stereoselective degradation in the body had significant influence on the disposition of SBPC epimers.

Sulbenicillin: pharmacokinetics and penetration into bronchial secretion in elderly patients.

This study evaluates the pharmacokinetics of sulbenicillin (alpha-sulfobenzylpenicillin) in elderly subjects after single and multiple doses and the penetration into bronchial secretion in elderly patients with chronically superinfected bronchial pathology. Peak plasma levels were 53.34 micrograms/ml (group I); 55.80 and 57.82 micrograms/ml (group II) after 1 h. The half-life (t 1/2 beta) was 1.47 h (group I); 1.49 and 1.62 h (group II). Renal clearance was 6.68 l/h; 6.25 and 5.44 l/h; whereas the volume of distribution was 18.02 l; 17.84 and 17.21 l for groups I and II respectively. The mean percentage of the recovered active drug in urine over 12 h was 77.72% of dose. The mean peak reaching the bronchial secretion was 3.60 micrograms/ml at the 4th hour. The results of the multiple dose study indicated that there was no apparent change in the distribution or elimination kinetics of sulbenicillin after 2 g i.m. administration. Thus, the kinetics from the multiple dose study were in close agreement with those from the single dose study and no accumulation of sulbenicillin was observed. This study provided satisfactory results and confirmed the significant presence of sulbenicillin into bronchial secretions.

Sulbenicillin-induced kaliuresis in man.

The mechanism of kaliuresis induced by massive antibiotic administration was studied using alpha-sulfobenzyl penicillin (SBPC). In experimental group (n = 8), urinary electrolytes excretion were compared between following the infusion of 10 g SBPC in 200 ml water at a constant rate and following the infusion of 48 mmol of NaCl (equal to that contained in 10 g SBPC) in 200 ml water. For the control group, 96 mmol NaCl in 400 ml water was infused (n = 5). In the experimental group, urinary Na (UNaV) and urinary K excretion (UKV) increased relative to the control period. In the control group, UKV was not increased although UNaV was increased (p less than 0.05). UKV following SBPC infusion was correlated with UNaV (p less than 0.05) and urinary SBPC excretion (p less than 0.05). The ratio of urinary anion gap to urinary cation [1-(urinary Cl concentration/(urinary Na concentration + urinary K concentration))] was significantly increased following SBPC infusion (p less than 0.005) but not in the control group. This increase in anion gap is possibly due to urinary SBPC, which will be ionized over 90% as nonreabsorbable anion in maximally acidic urine. We conclude that the kaliuresis induced by massive SBPC administration in man is probably caused by the nonreabsorbable anion effect of SBPC itself.

The influence of renal function on the elimination kinetics of sulbenicillin in man.

Serum concentration and urinary excretion following a single i.v. dose of 1 g Sulbenicillin (SB) have been studied in 13 subjects with different degrees of renal insufficiency and 4 control subjects. With normal GFR, serum half-life averages 27 min, with GFR between 45 and 14 ml/min, 1,5 hours, with GFR below 8-10 ml/min, 4,6 hours (maximum 7 hours). The usually recommended dosage schedule is 1 g every 6 hours. Only when GFR falls below 8-10 ml/min, the interval between doses must be changed; 1 g every 8-12 hours should be given under these conditions. However, in cases of severe extrarenal or urinary tract infections due to antibiotic-resistant strains of E. coli, Ps. aeruginosa, Pr. morganii, a first dose of 2-4 g SB should be given, followed by maintenance half-doses (1-2 g SB) every half-life.

High-performance liquid chromatographic analyses of sulbenicillin and carbenicillin in human urine.

A high-performance liquid chromatographic method has been developed for the determination of sulbenicillin (SBPC) and carbenicillin (CBPC) excreted in human urine. The method uses reversed-phase ion-pair chromatography with a bonded hydrophobic stationary phase and methanol-tetra-n-butylammonium bromide solution as the mobile phase. Urine is filtered through a micropore membrane and the filtrate introduced directly into a liquid chromatograph. An in vivo experiment was conducted by administering intravenously 1 g of SBPC or CBPC to volunteers and analysing their urine. One-compartment model analysis of the time-course data revealed that 73.1% of the amount of SBPC dosed was excreted in the urine with a rate constant of 0.579 h-1, and 91.5% of CBPC with a rate constant of 0.845 h-1.