Polyethylene Glycol 400 Enhances the Bioavailability of a BCS Class III Drug (Ranitidine) in Male Subjects but Not Females
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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.
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.
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.
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.
KEY WORDSexcipients gastrointestinal transit gender H2 receptor antagonists oral absorption metabolism permeability solubility efflux transporters
Diane A. I Ashiru gratefully acknowledges the Medical Research Council (MRC) and GlaxoSmithKline for the award of a studentship. In addition the authors thank Dr Erin Hugger at GlaxoSmithKline for her helpful discussions and comments. Dr Roger Jee at the School of Pharmacy, University of London is also acknowledged for his help with statistical analysis and interpretation.
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