Pharmacokinetics of amoxicillin coadministered with a saline‐polyethylene glycol solution in healthy volunteers

Abstract

The pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline-polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean +/- SD area under the curve was lower with SPG (43.8 +/- 6.8 against 47.8 +/- 8.2 mg h L-1, p < 0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.

Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs

“…This can be supported by the literature data on chlorthalidone, amoxicillin, and digoxin (30)(31)(32). As shown in Table III, addition of chlorthalidone powder to 10% PEG 4000-water solution (treatment C) decreased the AUC and urinary excretion of chlorthalidone compared to other treatments without PEG 4000.…”

“…Like sorbitol and mannitol, PEGs cannot be absorbed in the intestine and thus retains fluid by osmotic action. In this context, it was suspected that PEGs might interfere with the absorption of co-administered drugs through several mechanisms, including dilution, modification of solubility, direct action on intestinal mucosa, and acceleration of intestinal transit time (30). Additionally, PEGs have been demonstrated to interact with certain transporters, particularly efflux transporters such as Pglycoprotein (P-gp) (28).…”

“…5, there is a linear relationship between the osmotic potential of PEG 4000 and reduction in the bioavailability of drugs tested over the dose range of 2.95-10 g for PEG 4000. The intestinal transport of amoxicillin was mediated by both passive diffusion and active transport through a dipeptide carrier (30). Digoxin is known to be a sensitive P-gp substrate in vitro (35); however, its role as an in vivo probe substrate of P-gp has been questioned recently (36).…”

Development and Validation of Limited-Sampling Strategies for Predicting Amoxicillin Pharmacokinetic and Pharmacodynamic Parameters

“…A large number of plasma samples (n ϭ 1,152) collected from 48 closely monitored, healthy volunteers in two bioequivalence studies allowed the development and subsequent validation of LSS models by using several different procedures. The results show that the AUC 0-ϱ of amoxicillin, following administration of single oral doses (500 ) for amoxicillin in 11 previously published studies (1,3,7,10,13,14,(17)(18)(19)(20)26), and the corresponding AUC 0-ϱ derived from the three-point LSS model developed for the reference capsule formulation in the present study (Table 3, (Table 2). The statistical principle of parsimony advises in favor of models with fewer parameters; thus, we settled for three-sample regressions for independent estimation of amoxicillin's AUC 0-ϱ .…”

“…As a third test of the validity of the LSS models developed for estimating amoxicillin's AUC 0-ϱ , the most informative three-point LSS equation derived for the training data set (reference capsule formulation) was used to estimate the AUC 0-ϱ of subjects enrolled in 11 previously published studies after administration of single oral doses (250 to 1,000 mg) of various amoxicillin formulations (1,3,7,10,13,14,(17)(18)(19)(20)26). Scanned plots of the published AUCs were used to obtain the data points employed for the LSS-derived AUC 0-ϱ 's and to obtain the best estimated AUC 0-ϱ 's by means of the trapezoidal method.…”