Relative quantification of polyethylene glycol 400 excreted in the urine of male and female volunteers by direct injection electrospray-selected ion monitoring mass spectrometry.

The use of polyethylene glycol 400 (PEG 400) as an excipient in oral formulations can have profound and differing effects on drug bioavailability in men and women; therefore an understanding of the pharmacokinetics of this excipient is required. A direct injection electrospray selected ion monitoring mass spectrometry methodology was developed and validated for the quantitation of PEG 400 excreted in human urine after oral administration. The most abundant ions corresponding to PEG 400 oligomers at m/z 365, 409, 453, 497, 541, and 585 were used for selected ion monitoring (SIM). Pre-dose urine of volunteers was spiked with various amounts of PEG 400 to generate calibration curves over the concentration range 2.5-90 µg/mL for all SIM channels. The relative standard deviations of intra- and inter-day analysis of PEG 400 in human urine were lower than 11.8% and bias percentage was less than 9.7%. This specific method for relative quantitation of PEG 400 was then used to analyse urine samples with minimal sample preparation. Urine samples of twelve healthy volunteers (six men and six women) who received 0.75 g and 1.5 g PEG 400 on two separate occasions were collected over 24h. On average 36.5% of the orally administered dose of PEG 400 was recovered in the urine of the volunteers, with no significant difference observed between men and women.

Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females.

PURPOSE: The aim of this study was to investigate the effects of different doses of polyethylene glycol 400 (PEG 400) on the bioavailability of ranitidine in male and female subjects. METHOD: Ranitidine (150 mg) was dissolved in 150 ml water with 0 (control), 0.5, 0.75, 1, 1.25 or 1.5 g PEG 400 and administered to 12 healthy human volunteers (six males and six females) in a randomized order. The cumulative amount of ranitidine and its metabolites excreted in urine over 24 h was determined for each treatment using a validated HPLC method. RESULTS: In the male volunteers, the mean cumulative amount of ranitidine excreted in the presence of 0, 0.5, 0.75, 1, 1.25 and 1.5 g PEG 400 were 35, 47, 57, 52, 50 and 37 mg respectively. These correspond to increases in bioavailability of 34%, 63%, 49%, 43% and 6% over the control treatment. In the female subjects, the mean cumulative quantity of ranitidine excretion in the absence and presence of increasing amounts of PEG 400 were 38, 29, 35, 33, 33 and 33 mg, corresponding to decreases in bioavailability of 24%, 8%, 13%, 13% and 13% compared to the control. The metabolite excretion profiles followed a similar trend to the parent drug at all concentrations of PEG 400. CONCLUSIONS: All doses of PEG 400 enhanced the bioavailability of ranitidine in male subjects but not females, with the most pronounced effect in males noted with the 0.75 g dose of PEG 400 (63% increase in bioavailability compared to control, p < 0.05). These findings have significant implications for the use of PEG 400 in drug development and also highlight the importance of gender studies in pharmacokinetics.

Simple and universal HPLC-UV method to determine cimetidine, ranitidine, famotidine and nizatidine in urine: application to the analysis of ranitidine and its metabolites in human volunteers.

A validated, simple and universal HPLC-UV method for the determination of cimetidine, famotidine, nizatidine and ranitidine in human urine is presented. This is the first single HPLC method reported for the analysis of all four H(2) antagonists in human biological samples. This method was also utilized for the analysis of ranitidine and its metabolites in human urine. All calibration curves showed good linear regression (r(2)>0.9960) within test ranges. The method showed good precision and accuracy with overall intra- and inter-day variations of 0.2-13.6% and 0.2-12.1%, respectively. Separation of ranitidine and its metabolites using this assay provided significantly improved resolution, precision and accuracy compared to previously reported methods. The assay was successfully applied to a human volunteer study using ranitidine as the model compound.

Impact of formulation excipients on human intestinal transit.

The accelerating effect of polyethylene glycol 400 on small intestinal transit has been previously reported. The aim of this study was to investigate the influence of other solubility-enhancing excipient, propylene glycol, D-alpha-tocopheryl-polyethylene glycol-1,000 succinate (VitE-TPGS) and Capmul MCM, on human intestinal transit. A 5-g dose of each excipient was administered to seven healthy male subjects. Propylene glycol and VitE-TPGS were administered dissolved in 150 mL water. Capmul MCM was administered in the form of four 000 hard gelatin capsules to mask its taste and then given with 150 mL water. On a separate occasion, 150 mL water was administered as the control. Each formulation was radiolabelled with technetium-99 m to follow its transit using a gamma camera. The mean small intestinal transit times were 234, 207, 241 and 209 min for the control, propylene glycol, VitE-TPGS and Capmul MCM treatments, respectively. Although there were differences in the small intestinal transit times for the excipients investigated compared with the control, none of the results were statistically significant. Unlike polyethylene glycol 400 at the same dose of 5 g, the excipients tested (propylene glycol, VitE-TPGS and Capmul MCM) had little or no impact on small intestinal transit.