HUMAN INTESTINAL PERMEABILITY OF PIROXICAM, PROPRANOLOL, PHENYLALANINE, AND PEG-400 DETERMINED BY JEJUNAL PERFUSION

Purpose. To determine the human jejunal permeabilities of compounds ut ilizing different transport mechanisms using a regional perfusion appr oach and to establish a standard procedure for determining drug permea bility class to be used for the establishment of drug product bioequiv alence standards. Methods. Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and posi tioned in the proximal region of the jejunum. A solution containing pi roxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate sam ples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and i ntersubject variation. Results. The mean P-eff (+/-SD) Of piroxicam, p henylalanine, propranolol, and PEG 400 were 10.40 +/- 5.93, 6.67 +/- 3 .42, 3.59 +/- 1.60, 0.80 +/- 0.46 x 10(-4) cm/sec, respectively. The c oefficient of variation for the intersubject variability, first and se cond perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine , 52.8% and 57.8%: propranolol, 62.1% and 44.6%; and PEG 400, 81.7% an d 42.3%, indicating a slightly lower CV for the second perfusion perio d in the same subject. The intrasubject CV's between the two perfusion periods were: 19.4%, 21.3 %, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied. Conclu sions. Piroxicam, a nonpolar drug exhibited the highest permeability o f the compounds studied. The intrasubject CV was lower than the inters ubject CV, indicating consistent permeability estimation within subjec ts. The methodology is useful for permeability estimation regardless o f absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption a nd for establishing the biopharmaceutic permeability class of drugs.