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4-Hydroxy-3-methoxymandelic acid and 3,4-dihydroxymandelic acid were found to be potent adjuvants for the rectal absorption of water-soluble compounds in rats. Both adjuvants enhanced the absorption of two cephamycin antibiotics, cefmetazole and cefoxitin. Maximum plasma levels of the antibiotics were obtained within 30 min after rectal administration. The bioavailability of both antibiotics appeared to depend on the concentration of the adjuvant in the microenema, the dosage form used in these experiments. Instead of a microbial assay, a new chemical method involving high-performance liquid chromatography with an ion-pairing technique was developed for analyzing the cephamycin antibiotic plasma levels.

The mechanism underlying the ability of phosphate derivatives to act as adjuvants and coadjuvants was examined in in vivo and in situ preparations in rats and dogs. The adjuvant effect of DL-alpha-glycerophosphate on the rectal absorption of sodium cefoxitin was greatly augmented by the presence of either sodium phytate or sodium tripolyphosphate. These coadjuvants only slightly enhanced cefoxitin rectal absorption when administered alone. Therefore, enhancement of the permeation of tripolyphosphate and phytate by alpha-glycerophosphate may be necessary before the coadjuvants can significantly affect cefoxitin absorption. The inhibitory effect of disodium 4,4'-diisothiocyano-2,2'-disulfonate stilbene, which is known to interact with the amino group in the protein fraction, on enhanced cefoxitin absorption suggests the involvement of the protein fraction in transport of cefoxitin across the rectal membrane.

The disappearance of phenylalanine and phenylalanylglycine from a perfusate circulated across rat rectal tissue was enhanced significantly in the presence of salicylate or 5-methoxysalicylate at pH 4.5, 7.4, and 8.5. The disappearance of di-, tri-, and tetraphenylalanine from a perfusate at pH 7.4, although facilitated by the presence of salicylate and 5-methoxysalicylate, was also fairly substantial when no adjuvant was present. These peptide analogues of phenylalanine also enhanced the rectal absorption of cefoxitin and cefmetazole, two highly water soluble antibiotics. Phenylalanine and phenylalanylglycine, both poorly absorbed across the rectal membrane when administered alone, did not enhance the rectal absorption of either antibiotic.