Transdermal Absorption Kinetics - ACS Symposium Series (ACS

2 Transdermal Absorption Kinetics A Physicochemical Approach 1

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RICHARD H.GUY ,JONATHAN HADGRAFT , and HOWARD I. MAIBACH 1

Departments of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, University of California Medical Center, San Francisco, CA 94143 Department of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom Department of Dermatology, School of Medicine, University of California Medical Center, San Francisco, CA 94143

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Downloaded by COLUMBIA UNIV on March 9, 2013 | http://pubs.acs.org Publication Date: February 25, 1985 | doi: 10.1021/bk-1985-0273.ch002

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The development of a biophysically based model of chemical absorption via human skin is described. The simulation has been used to analyze the in vivo penetration kinetics of a broad range of molecular species. Four first-order rate constants are identified with the percutaneous absorption process: k penetrant diffusion through the stratum corneum; K transport across the viable epidermal tissue to the cutaneous microcirculation; k - a retardation parameter which delays the passage of penetrant from stratum corneum to viable tissue; k - the elimination rate constant of chemical from blood to urine. Interpretation of urinary excretion data following topical application is presented for 9 compounds. It is shown that the model has predictive potential based upon recognized cutaneous biology and penetrant physical chemistry, in particular the diffusive and partitioning properties of the substrate. Refinements and developments of the approach (e.g., to multiple exposure and competitive surface removal situations) are indicated and discussed. 1

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Occupational disease, caused by skin contact with toxic substances, represents a major health problem i n the United States (1). Dermal exposure of a g r i c u l t u r a l workers to pesticide agents, of course, i s a p a r t i c u l a r l y pertinent example of this problem. Prediction of the detrimental toxic effects of hazardous chemical exposure i s d i f f i c u l t , however, because of the complexity of the percutaneous absorption process i n man and a lack of any consistently i d e n t i f i a b l e relationship(s) between transport rate and chemical properties. In addition, the very diverse approaches, which have been used to measure skin penetration, further complicate the situation since the extrapolation of results to man i n his workplace may involve questionable, non-validated assumptions. Our s p e c i f i c aim i s to predict accurately the toxicokinetics of occupationally-encountered molecules ( e . g . , pesticides) absorbed across human skin in v i v o . We present 0097-6156/85/0273-0019$06.00/0 © 1985 A m e r i c a n C h e m i c a l Society

In Dermal Exposure Related to Pesticide Use; Honeycutt, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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DERMAL EXPOSURE RELATED TO PESTICIDE USE

here the application of a novel k i n e t i c model (to analyze previously published data) which suggests that the health hazard from cutaneous exposure to toxic chemicals may be predicted correctly on the basis of fundamental b i o l o g i c a l and physicochemical p r i n c i p l e s .


The Kinetic Model The simulation i s depicted i n Figure 1 ( 2 ) . The model i s linear and i d e n t i f i e s four k i n e t i c processes to describe a penetrant's transport through, retention i n , and removal from the skin and body. k^ characterizes transport of penetrant across the stratum corneum and assumes negligible "vehicle" e f f e c t s . Such an approach i s reasonable f o r skin contact with pure liquids and materials or with v o l a t i l e solvents which s o l u b i l i z e the potential penetrant. More complicated vehicles or penetrant delivery systems w i l l require a separate input function to be added to the model. Because of the passive nature of the stratum corneum barrier (3), we may relate k^ to the substrate's d i f f u s i o n c o e f f i c i e n t (D^) through this outermost skin layer. Hence, i n turn, k^ can be shown to be penetrant molecular weight (M) dependent v i a the Stokes-Einstein relationship (4): k

= C.D

x

L

= c'(Mr

(1)

1 / 3

where C and C are constants. I f k^ i s known f o r one or more substances, then i t s value f o r a new or different molecule may be evaluated using Equation 1 (assuming ( i ) that the transport mechanism remains unaltered, and ( i i ) that the p a r t i a l s p e c i f i c volumes of the penetrants are approximately equivalent), i . e . , k

U

= k* ( M / M )

(2)

1/3

where the superscripts u and k refer to the molecules whose kj values are unknown and known, respectively. In this paper, we have u t i l i z e d an experimental estimate of k^ f o r benzoic acid (5) to determine k^ values f o r the other penetrants discussed. k describes penetrant d i f f u s i o n through viable epidermal and dermal tissue to the cutaneous blood vessels and systemic c i r c u l a t i o n . Again, we equate k2 with the corresponding d i f f u s i o n c o e f f i cient (D2) and substrate molecular weight v i a an equation analogous to Equation 1 : 2

k

2

= C".D

f

2

= C "(M)"

1 / 3

(3)

C and C' ' are constants. Previous estimates of k (2) have shown that the rate constant r e f l e c t s a d i f f u s i v e process with D - 10 cm s , a value consistent with the perception of this tissue region as an aqueous protein g e l ( 6 ) . kg plays a decisive role i n determining the f i n a l k i n e t i c p r o f i l e by r e f l e c t i n g the competition f o r penetrant between hydrophobic stratum corneum and the more aqueous viable tissue, k^ acts, therefore, as a retardation rate constant ( i . e . , the greater k^, the longer the penetrant i s held up i n the horny layer and the slower i t partitions into the viable t i s s u e ) . The magnitude of k^ can, i n this 1

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2.

GUY

Transdermal

ET AL.

Absorption

21

Kinetics

way, signify the p o s s i b i l i t y of penetrant binding to skin or the l i k e l i h o o d of a "reservoir" effect (7). k^ can, furthermore, correct for the s i m p l i s t i c relationship between kj and M. A high value of kg, for example, may be used to imply very slow stratum corneum d i f f u s i o n , because of increased interaction between penetrant and tissue. If such an assignation i s accepted, then the r a t i o becomes a measure of an "effective p a r t i t i o n c o e f f i c i e n t " for the penetrant between stratum corneum and viable tissue. As i s shown below, this interpretation provides important and s i g n i f i c a n t predictive power to the simulation. k^ describes penetrant removal from the body once the chemical has reached the dermal vasculature. Compound i n the cutaneous micro c i r c u l a t i o n i s not differentiated from that i n the systemic pool, k^ i s equated, therefore, with the elimination rate constant (or combi nation of constants) that would be obtained i f the penetrant were administered intravenously. Four d i f f e r e n t i a l equations describe mathematically the model shown i n Figure 1 (2). These expressions relate to the rates of change of penetrant concentration on and within the skin, i n the blood and i n the urine. Solution i s straightforward and gives the following equation for , the amount of penetrant appearing i n the urine as a function of time ( t ) : t

*t

=

F k

k

k

l 2 4

{

1

/

o

i

6

k

i

~ e x p ( - k t ) / [ k ( k - α ) ( ^ - 3)1 1

1

1

exp(-at)/[a(a-3)(a-k )] - exp(-$t )/[ 3( 3 " ^ ) ( $-a) ] } 1

(4)

F i s the f r a c t i o n of the t o t a l amount of penetrant i n contact with the skin at t=0 which eventually penetrates, and α and 3 s a t i s f y the relationships: a3 = k k 2

(5)

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(6) k + k, 4 Equation 4 allows determination of % dose excreted per unit time for any specified times and we have made such calculations to coincide with the experimental data, which i s interpreted below. (a+3) - k + 2

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Data Interpretation The k i n e t i c model has been used to analyze percutaneous penetration rate data for nine molecules: a s p i r i n , benzoic acid, caffeine, chloramphenicol, diethyltoluamide, nitrobenzene, s a l i c y l i c acid (8) and the methyl and benzyl esters of n i c o t i n i c acid (9)· Experi mentally, the chemicals ( C - l a b e l l e d ) were applied t o p i c a l l y i n acetone to the ventral forearm of human volunteers and the urinary excretion of r a d i o a c t i v i t y was then measured over a f i v e day period; F values were thus determined d i r e c t l y , k^ parameters for these molecules were also assessed by monitoring urinary excretion following intravenous administration of a ^ C - l a b e l l e d dose (8). T y p i c a l l y , k^ and F values are associated with a standard deviation of 10-15% (8). The experimental results are plotted i n Figures 2-10; on each figure, calculated urinary excretion rates are also given 14


DERMAL EXPOSURE RELATED TO PESTICIDE USE

SKIN SURFACE

STRATUM CORNEUM

VIABLE EPIDERMIS

BLOOD

•

URINE


K i - H

F i g u r e 1.

»

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The p h a r m a c o k i n e t i c

model.

ΐ

TIME

Transdermal Absorption Kinetics - ACS Symposium Series (ACS

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