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In v i t r o methods using both human and animal skin a r e becoming more widely used f o r attempting t o predict t h e 1 i kely percutaneous absorption of drugs and industrial chemicals to.which man .is exposed (Michaels e t a l , 1975; Bronaugh e t a1 , 1984). However, wide variations i n methodology between workers and l a r g e intersubject differences in permeabil i t y 1 imit t h e value of current d a t a f o r q u a n t i t a t i v e relationships between permeation and s t r u c t u r e t o be established.Our s t r a t e g y has been t o standardise t h e methodology by appl ing compounds in suspension a t ten times t h e i r s o l u b i l i t y in l i h t l i q u i d parafAn B.P. ( L L P ) , an i n e r t non-penetrating vehicle.This approac! not only maintains t h e stratum corneum under r e l a t i v e l y normal conditions throughout an ex eriment b u t a l s o enables a tru steady-state penetra ion r a t e t o be defined. T ree radiolabelled were each studied on eleven d i f f e r e n t donor skins.compounds, [f4C]caffeine ( C ) , [ l k Cltestosterone ( T ) and [ Hloestradiol ( 0 ) Equilibrated sus ensions of C , T and 0 in LLP a t concentrations o P were appl ied ( l O '~& n % r~) t o human abdomi nay epidermal membranes he1 d in horizontal open-top diffusion c e l l s with hosphate buffered s a l i n e ( H 7.4) containing 6% (wfv) PEG-20 .ole11 ether as tRe receptor medium.Cells were maintained . i n a water bath a t 37°C f o r f i v e days during which time samples were removed from t h e receptor compartment a t regular i n t e r v a l s and assayed f o r radioactivitf. For each c e l l a permeability constant (Kp, cm h-) was calculated from t h e relevant saturated solution concentration (ug cm-3) a d the steady-state absorption r a t e ( u g cm-2 h-f) determined from t h e l i n e a r portion of the absorption p r o f i l e by regression analysis.f o r C ranged between 0.9 and 7.1 (cm h-1 x ; an eightfold difference between t h e highest owest. and 0 ; tenfold and nineteenfold respectively. However, 1 inear regression analysis revcaled t h a t an intersample r e l a t i o n s h i p existed. between Kp's f o r C , T and 0 with correlation c o e f f i c i e n t s ( r ) of 0.93. Normalisation of t h e Kp data on each sample t o t h a tof t h e mean value f o r C , t h e most rapid penetrant, resulted i n a s i a n i f i c a n t imwovement in t h e Therefore, by using t h e above method and, f o r each donor skin in a study includin a standard penetrant e i t h e r in admixture with t h e t e s t compounds o r se arateyy, intersampl e variations i n percutaneous absorption can be reduced t o a fevel where s t u d i e s can be d i r e c t l y compared. Furthermore, t h i s method .may permit real i s t i c redictions of human percutaneous absorption from in v i t r o studies with animaf skin.[n = 111 Michaels, A.S. e t a1 (1975). Am. Inst. Chem. Eng. 21: 985 Bronaugh, R. e t a1 (1984). J . Pharm. Sci. 73:1255Sci. 73: -1258