Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium taurocholate as natural model surfactant: studies in rat colon and in rat duodenum.

The influence of the natural bile acid surfactant sodium taurocholate (CAS 81-24-3) on colic and duodenal (i.e. the proximal third of the small intestine) absorption of cefadroxil (CAS 50370-12-2) was studied using the in situ rat gut technique, and compared with the effect of sodium lauryl sulfate (CAS 151-21-3), the most widely used synthetic anionic surfactant. Previously, the stability, compatibility, and micelle-solubilization characteristics of taurocholate were assessed in order to correct, when necessary, the absorption results. White the passive absorption rate constants (kf, h-1) determined in colon in the presence of increasing lauryl sulfate concentrations showed an asymptotic value about 7-fold higher than that of cefadroxil alone, only a 2-fold higher value was obtained in the presence of taurocholate at similar concentrations. Therefore the natural surfactant would increase the polarity of the colic absorbent membrane much less than lauryl sulfate does (about 3.5 times). The effects of taurocholate on the duodenal absorption of cefadroxil, which is the sum of a single passive process and a simultaneous carrier-mediated transport, can be summarized as follows: 1. When the working concentration of cefadroxil is far from carrier saturation (0.1 mg/ml) a slight but clear net decrease in the apparent kf value is observed in the presence of increasing concentrations of the natural surfactant (from 3.0 to 2.3 h-1) 2. When the concentration of the antibiotic in the working fluid is above carrier saturation (10 mg/ml) the picture is reversed, and a slight net increase in kf in the presence of increasing concentrations of taurocholate (from 0.8 to 1.2 h-1) is found. This means that the effect of taurocholate as a noncompetitive inhibitor of active cefadroxil transport is very much smaller than that observed with lauryl sulfate. Moreover, the increase in passive absorption relative to the synthetic surfactant is also much smaller. On the basis of allometric considerations it could be concluded that for practical purposes taurocholate does not act as a substantial absorption modifier for cefadroxil, at least in the small intestine, the main absorption site of the antibiotic. It can, however, not be considered an inert ingredient, and therefore oral administration of cefadroxil far from that of taurocholate-containing preparations, and even from lipid-rich meals should be strongly recommended.

Pharmacokinetics of netilmicin during hemodialysis: comparison of four artificial kidneys.

The pharmacokinetics of netilmicin was studied in 11 patients with terminal renal impairment (Clcr less than 5 ml/min) during the course of a 4-h hemodialysis session, using four different kinds of dialyzer: Biospal 2400, Biospal 3000, Allegro HF, and Andante HF. All patients received a single dose of 2 mg netilmicin/kg body wt at the beginning of the dialysis session. The type of dialyzer influences the serum half-life, the dialysis clearance and the percentage of drug extracted during dialysis. A linear relationship was established between the drug fraction extracted by dialysis and the dialysis clearance of the antibiotic. During the hemodialysis sessions, the serum half-life of netilmicin decreased approximately 10-fold compared with the interdialysis periods.

Pharmacokinetics of netilmicin in renal insufficiency and hemodialysis.

The pharmacokinetics of netilmicin was studied in 26 patients with varying degrees of renal impairment (11 were dialysis patients) in order to determine the influence of kidney function status on the disposition of the antibiotic. The serum level curves of netilmicin follows a two-compartment open kinetic model. Several relationships between pharmacokinetic parameters and renal function indicators are defined. A clinical useful correlation indicates that the half-life is approximately 3 times the serum creatinine concentration, and may be used for adjusting the netilmicin dosage in the treatment of patients with impaired renal function. During hemodialysis the serum half-life decreases approximately 10-fold compared with the interdialysis periods. The percentage of dose extracted by hemodialysis during a single 4 h session is 56.1 +/- 6.65%. The dialysis clearance is 87.28 +/- 28.8 ml/min.