Table 4sDermal/Transdermal Delivery Ratios (D/T) and Log
solvent (Th/PG) were not different from the Th/PG flux
after application of 5-FU/IPM. The 1-ACOM-5-FU series
was relatively more effective at delivering total 5-FU
species through the skin than at delivering total 5-FU
species into the skin compared with 5-FU based on the
ratios of Cs values to J i values (D/T delivery ratios). The
1-ACOM-5-FU prodrugs were generally less effective than
the 1-AC-5-FU prodrugs when members from each series
of equal alkyl chain length were compared based on J i
values. On the other hand, if the CH2O spacer was taken
into account, the 1-ACOM-5-FU prodrugs were generally
more effective than the 1-AC-5-FU prodrugs.
Permeability Coefficients (log Pi) for 1-ACOM-5-FU Prodrugs, and Log
Pi, Ji, SIPM, and SH Values for 1-AC-5-FU Prodrugs
O
2
c
c
log Pi,b
cm/h
log Pi,b,c
cm/h
Ji,c
SIPM
,
SH ,
O
2
alkyl
)
D/Ta
µ
mol/cm2h
mM
mM
5-FU
CH3
C2H5
C3H7
C4H9
C5H11
C7H15
0.13
0.69
s
s
s
s
120.
0.015
0.022
0.029
0.045
0.099
0.20
−0.06
−0.41
−0.75
−1.06
−1.42
−1.92
−2.46
−1.41
−0.38
−0.93
−1.13
−1.59
−2.01
−2.27
−
2.66d
9.3
4.4
1.3
1.0
1.1
0.60
0.13d
s
22.1
36.4
17.4
39.2
112.7
110.7
59.0d
s
47.6
6.50
3.48
2.94
0.15
sd,e
s
C9H19
(CH3)3C
0.91
0.17
s
References and Notes
a Calculated from [CS/(4.9 cm2 24 h)]/Ji to give dimensionless ratio.
b Calculated from Ji/SIPM c From ref 7. d From ref 24. e Could not be estimated.
1. Dillaha, C. J .; J ansen, G. T.; Honeycutt, W. M.; Holt, C. A.
Arch. Dermatol. 1965, 92, 410-417.
.
2. Robinson, T. A.; Kligman, A. M. Br. J . Dermatol. 1975, 92,
703-706.
significant differences between the J j values obtained after
the application of the prodrugs/IPM and after the applica-
tion of 5-FU/IPM. Thus, if J j values are used as measure
of relative damage,16 there are no differences in the damage
caused by the application of the prodrugs/IPM, and the
differences in J i are due to differences in the abilities of
the prodrugs to deliver 5-FU.
3. Goodman, M.; Barry, B. W. J . Invest. Dermatol. 1988, 91,
323-327.
4. Mollgaard, B.; Hoelgaard, A.; Bundgaard, H. Int. J . Pharm.
1982, 12, 153-162.
5. Sloan, K. B.; Koch, S. A. M.; Siver, K. G. Int. J . Pharm. 1984,
21, 251-264.
6. Beall, H.; Prankerd, R.; Sloan, K. B. Int. J . Pharm. 1994,
111, 223-233.
7. Beall, H.; Sloan, K. B. Int. J . Pharm. 1996, 129, 203-210.
8. Beall, H. D.; Prankerd, R. J .; Sloan, K. B. Drug Dev. Ind.
Pharm. 1996, 22, 85-90.
A plot of the log permeability constants (log Pi, Table 4)
for the delivery of total 5-FU species through hairless
mouse skin against the calculated solubility parameters
for the corresponding 1-ACOM-5-FU prodrugs (δi, data not
shown) gives a curve (plot not shown) that is similar to
that observed for the ACOM prodrugs of 6-MP.23 The log
Pi values for the delivery of 5-FU by the 1-alkylcarbonyl-
5-FU prodrugs (1-AC-5-FU)7 have been included in Table
4 to allow for convenient comparison of the 1-ACOM-5-FU
series with the best series of the 1-acyl-type prodrugs of
9. Buur, A.; Bundgaard, H.; Falch, E. Int. J . Pharm. 1985, 24,
43-60.
10. Taylor, H. E. Ph.D. Dissertation, University of Florida, 1997.
11. Bigler, P.; Schonholzer, S.; Neuenschwander, M. Helv. Chim.
Acta 1978, 61, 2059-2080.
12. Ozaki, S.; Watanabe, Y.; Hoshiko, T.; Mizuno, H.; Ishikawa,
K.; Mori, H. Chem. Pharm. Bull. 1984, 32, 733-738.
13. Sloan, K. B.; Beall, H. D.; Weimar, W. R.; Valleneuva, R.
Int. J . Pharm. 1991, 73, 97-104.
14. Fedors, R. F. Polym. Eng. Sci. 1974, 14, 147-154.
15. Martin, A.; Wu, P. L.; Velasquez, T. J . Pharm. Sci. 1985,
74, 277-282.
16. Sloan, K. B.; Koch, S. A. M.; Siver, K. G.; Flowers, F. P. J .
Invest. Dermatol. 1986, 87, 244-252.
17. Ahmad, S.; Ozaki, S.; Nagase, T.; Iigo, M.; Tokazen, R.; Hoshi,
A. Chem. Pharm. Bull. 1987, 35, 4137-4143.
18. Ozaki, S.; Nagase, T.; Tamai, H.; Mori, H.; Hoshi, A.; Iigo,
M. Chem. Pharm. Bull. 1987, 35, 3894-3897.
19. Ulich, L. H.; Adams, R. J . Am. Chem. Soc. 1921, 43, 660-
667.
5-FU. Also included are J i, SIPM, and SH values for the
2O
1-AC-5-FU series. In comparisons of log Pi for equal-length
alkyl chain prodrugs from the two series, the 1-AC-5-FU
series always gives smaller log Pi values. This result is
because 1-AC-5-FU prodrugs exhibit larger SIPM values,
because, except for the C3 and C4 members, the J i values
for the 1-AC-5-FU series are larger.7 The C3 and C4
members of the 1-AC-5-FU series are anomalies because
they exhibit smaller SH and SIPM values than expected
2O
for their positions in the series and their poorer biphasic
solubilities lead to smaller J i values than expected.7 Thus,
for members of equal-length alkyl chains, the 1-AC-5-FU
series is generally more effective than the 1-ACOM-5-FU
series, despite exhibiting smaller Pi values.
20. Davidson, S. K.; Summers, J . B.; Albert, D. H.; Holms, J .
H.; Heyman, H. R.; Magoc, T. J .; Conway, K. G.; Rhein, D.
A.; Carter, G. W. J . Med. Chem. 1994, 37, 4423-4429.
21. Kamata, S.; Haga, N.; Matsui, T.; Nagata, W. Chem. Pharm.
Bull. 1985, 33, 3160-3175.
22. J encks., W. P.; Regenstein, J . In Handbook of Biochemistry
and Molecular Biology; Physical and Chemical Data, 2nd ed.;
Sober, H. A., Ed.; CRC: Cleveland, OH, 1970; pp J 188-J 226.
23. Waranis, R. P.; Sloan, K. B. J . Pharm. Sci. 1988, 77, 210-
215.
However, the ACOM-type promoiety contains an extra
CH2 and an extra O group, each of which extend the alkyl
chain and removes it farther from the 5-FU ring than the
AC-type promoiety of equal alkyl chain length. These extra
groups allow the effect of the van der Waals attraction
between the alkyl chains to become predominant sooner
in the 1-ACOM homologous series. Thus, the SIPM values
decrease significantly after the C7 member of the 1-AC
series, whereas SIPM values decrease after the C5 member
of the 1-ACOM series. If a similar displacement of the
comparison of J i values for the members of each series is
made, then the 1-ACOM type prodrug does give larger J i
values than the 1-AC type.
Con clu sion ssFor the 1-ACOM-5-FU series of prodrugs,
all of which are more lipophilic than 5-FU, the more water-
soluble members are the more effective ones at delivering
total 5-FU species from IPM through hairless mouse skin.
The differences in delivery are not due to differences in
damage caused by the different prodrugs/IPM because
fluxes from the subsequent application of a standard solute/
24. Patrick, A. I.; Beall, H. D.; Gilroy, P.; Sloan, K. B. Int. J .
Pharm. 1997, 154, 39-48.
25. Yalkowsky, S. H. In Design of Biopharmaceutical Properties
through Prodrugs and Analogues; Roche, E. B., Ed.; Ameri-
can Pharmaceutical Association Academy of Pharmaceutical
Sciences: Washington, D. C., 1977; pp 392-408.
26. Yalkowsky, S. H.; Flynn, G. L.; Slunick, T. G. J . Pharm. Sci.
1972, 61, 852-857.
27. Charton, M. J . Am. Chem. Soc. 1975, 97, 1552-1556.
28. Sheretz, E. F.; Sloan, K. B.; McTiernan, R. G. Arch. Dermatol.
Res. 1990, 282, 463-468.
29. Sheretz, E. F.; Sloan, K. B.; McTiernan, R. G. J . Invest.
Dermatol. 1987, 89, 147-151.
Acknowledgments
These studies were supported by NIH grant R15 CA 67230.
J S9702574
20 / Journal of Pharmaceutical Sciences
Vol. 87, No. 1, January 1998