Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG 400 determined by jejunal perfusion.
OBJECTIVE
To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards.


METHODS
Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation.


RESULTS
The mean P(eff) (+/-SD) of piroxicam, phenylalanine, 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 coefficient of variation for the intersubject variability, first and second 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% and 42.3%, indicating a slightly lower CV for the second perfusion period 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.


CONCLUSIONS
Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.
Takamatsu
N
N
Yamanouchi Pharmaceutical Co. Ltd., Shizuoka, Japan.
Welage
L S
LS
Idkaidek
N M
NM
Liu
D Y
DY
Lee
P I
PI
Hayashi
Y
Y
Rhie
J K
JK
Lennernäs
H
H
Barnett
J L
JL
Shah
V P
VP
Lesko
L
L
Amidon
G L
GL
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001682:Biological Availability; D006801:Humans; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D010539:Permeability / Q000187:drug effects; D010649:Phenylalanine / Q000493:pharmacokinetics*; D010894:Piroxicam / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011433:Propranolol / Q000493:pharmacokinetics*; D012997:Solvents / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012997:Solvents; D010894:Piroxicam; D011092:Polyethylene Glycols; D010649:Phenylalanine; D011433:Propranolol