Table 111-Effect of 4,4'-Diisothiocyano-2,2'di~lfonnte Stilbene (11) and Calcium Chloride (111) on tbe Enhancement of Plasma Cefoxitln Levels and on Cefoxitin Disappearance from the Rat Rectal In Situ Loop by a-Glycerophosphnte (I), Sodium Tripolyphosphate, and Sodium Phytate' Adjuvant Additive Concentration Concentration None None I(205 mM) None Tripolyphosphate None I I (1 mg/mL) 111 (l8OmM) (108 mM) I1 ( I mg/mL) 111 (l8OmMb Phytate (53 mM) None 11 ( 1 mg/mL) 111 (180 mM) Percent Disappearance of Cefoxitin at 1.5 h 5.4 f 5.8 38.7 f 8.1 16.8 f 6.3b 25.2 f 5.3 18.5 f 4.2 2 1 . 9 f 7.1 21.8 f 5.1 22.5 f 5.4 7.6 t 3.9b 7.8 f 3.2b <13b 119 f 28/, 5 2 f I I 9 9 f 18 61 f I I 66 f <I3 67 f 8 77 f 12 <13b 0 Micrememas contained 15 mg of cefoxitin/mL and had a dosage volume of 100 fiL/lOO g of rat body weight; n 2 3. b p < 0.001 uersus adjuvant without additive.
difference in their ability to permeate the rat rectal tissue. In the present study, we found that the coadjuvants tripolyphosphate and phytate substantially enhanced the absorption of cefoxitin only after their own permeation of the membrane was apparently enhanced by I. Thus, we speculate that adjuvant permeation of the mucosal membrane may be mechanistically necessary before enhanced compound absorption acrass the rectal membrane can occur.
In conclusion, the enhancing action of I on rectal cefoxitin absorption appears to depend on the affinity of I to the protein fraction in the mucosal membrane. The weak enhancing ability of the phosphate coadjuvants when administered with cefoxitin alone may involve chelating activity and possible damage to the rectal mucosa. However, the large increase in drug absorption after coadministration of I with either chelating agent, tripolyphosphate or phytate. is not just a consequence of the added effect of the enhancing action of 1 and chelation. These phosphate derivatives apparently have a strong adjuvant efficacy which can be realized only when their own permeation of the mucosal membrane is enhanced by adjuvants such as I.