title: Sex differences in excipient effects: Enhancement in ranitidine bioavailability in the presence of polyethylene glycol in male, but not female, rats.
abstract: Males and females respond differently to drugs: indeed, sex plays a crucial role in determining drug pharmacokinetics and pharmacodynamics. Excipients have also been shown to enhance the biovailability of drugs differently in men and women. The aim of this work was to investigate whether rodents are a good model in which to study sex-specific effects of polyethylene glycol 400 (PEG 400) on the bioavailability of ranitidine. Ranitidine (50mg/kg) was dissolved in water with different amounts of PEG 400-0 (control), 13, 26, 51, 77, 103, and 154mg/kg; these solutions were dosed orally by gavage to male and female Wistar rats. Blood samples were withdrawn over 480min and assayed via HPLC-UV. Individual ranitidine plasma profiles were constructed for each rat, and standard pharmacokinetic parameters were determined. In the male rats, the change in the area under the plasma ranitidine curve (AUC0-480) compared to the control group, was +18%; +49% (p<0.05); +37% (p<0.05); +31% (p<0.05); +8% and -22% (p<0.05) for PEG 400 doses of 13; 26; 51; 77; 103; and 154mg/kg respectively. On the other hand, females showed no statistically significant difference between the groups. In conclusion, low doses of PEG 400 enhanced the bioavailability of ranitidine in male, but not female, rats. These findings are in agreement with previously published human data, therefore confirming the validity of the rodent model, and highlight the unusual and clinically significant phenomenon that an excipient can influence drug bioavailability in one gender and not the other.
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK; Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Afonso-Pereira
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Sudaxshina
authors.initials: S
authors.lastname: Murdan
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Sousa
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Veiga
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK. Electronic address: a.basit@ucl.ac.uk.
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D005079:Excipients / Q000737:chemistry*; D005260:Female; D008297:Male; D023421:Models, Animal; D011092:Polyethylene Glycols / Q000737:chemistry*; D011899:Ranitidine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors
chemical_list: D005079:Excipients; D011092:Polyethylene Glycols; D011899:Ranitidine
keywords: Bioavailability; Gender; P-glycoprotein; Polyethylene glycol 400; Polyoxyethylene polymers; Ranitidine