N,N'-Dialkylaminoalkylcarbonyl (DAAC) prodrugs and aminoalkylcarbonyl (AAC) prodrugs of 4-hydroxyacetanilide and naltrexone with improved skin permeation properties.

N,N'-Dialkylaminoalkylcarbonyl (DAAC) and aminoalkylcarbonyl (AAC) prodrugs of phenolic drugs acetaminophen (APAP) and naltrexone (NTX) are reported. The effects of incorporation of a basic amine group into the promoiety of an acyl prodrug of a phenolic drug on its skin permeation properties are also presented. DAAC-APAP prodrugs were synthesized via a three-step procedure starting with haloalkylcarbonyl esters which were reacted with five different amines: dimethylamine, diethylamine, dipropylamine, morpholine, and piperidine. The spacing between the amino group and the carbonyl group of the acyl group was 1-3 CH(2). After the hydrolysis of the ester, the carboxylic acid product was subsequently coupled with the parent drug via a dicyclohexyl carbodiimide (DCC) mediated coupling to yield the DAAC-APAP-HCl prodrugs in excellent yields. The AAC prodrugs were synthesized using commercially available Boc-protected amino acids using DCC or EDCI as coupling agents. The yields of the prodrugs synthesized using these two different methods have been compared. Half-lives (t(1/2)) of a few members of the DAAC and AAC series were measured in buffer (pH 6.0, 20mM). The members evaluated in hydrolysis experiments exhibit a t(1/2) range of 15-113min. Among AAC-APAP prodrugs, the isopropyl group in valinate-APAP-HCl exerted a steric effect that increased the t(1/2) value for this prodrug compared to alaninate-APAP-HCl or prolinate-APAP-HCl. The 2-morpholinylacetate-APAP prodrug was able to achieve twice the flux of APAP in in vitro diffusion cell experiments through hairless mouse skin.

A correlation of flux through a silicone membrane with flux through hairless mouse skin and human skin in vitro.

The maximum fluxes of 32 prodrugs and parabens through polydimethylsiloxane membranes from water (EXP log J(MPAQ)) have been correlated with the maximum flux of the same prodrugs and parabens through hairless mouse skin from water (EXP log J(MMAQ)): EXP log J(MMAQ)=0.608 EXP log J(MPAQ)-0.636, r(2)=0.743. The average of the absolute values for the differences between the EXP log J(MMAQ) and the log J(MMAQ) calculated from EXP log J(MPAQ) (Delta log J(MMAQ)) was 0.227 log units. Similarly the maximum fluxes of 11 unrelated permeants through human skin from water (EXP log J(MHAQ)) was correlated with the EXP log J(MPAQ) for the same permeants: EXP log J(MHAQ)=0.516 EXP log J(MPAQ)-0.922, r(2)=0.82 and Delta log J(MHAQ)=0.252 log units. Since the best fit of the databases for EXP log J(MPAQ), log J(MMAQ) and log J(MHAQ) was to the Roberts-Sloan (RS) model, and the dependency of RS on a balance in lipid and aqueous solubility for optimization of topical delivery has been established, the present correlation suggests that the flux through a silicone can be used to predict flux through mouse or human and that the physicochemical properties that lead to optimized flux through one membrane will lead to optimized flux through the others.

A comparison of the fit of flux through hairless mouse skin from water data to three model equations.

Data for the delivery of total species containing parent drugs from water through hairless mouse skin by prodrugs, logJ(MMAQ), has been fitted to the Roberts-Sloan, RS, the Kasting-Smith-Cooper, KSC, and Magnusson-Anissimov-Cross-Roberts, MACR, equations. The RS model which contains a parameter for the dependence of flux on solubility in water, S(AQ), as well as solubility in the lipid isopropyl myristate, S(IPM), gave the best fit: logJ(MMAQ)=-2.30+0.575 logS(IPM)+0.425 logS(AQ)-0.0016MW, r(2)=0.903. The values for the coefficients to the parameters are quite similar to those obtained when the RS model was fit to flux of solutes from water through human skin, logJ(MHAQ). There was no trend in predicting the under or over-performance of prodrugs based on their fit to the RS model and whether they were more or less soluble than their parent drugs. There was an inverse dependence of logJ(MMAQ) on partition coefficients or permeability coefficients similar to that observed for logJ(MHAQ). The similarities in trends for results for logJ(MMAQ) and logJ(MHAQ) suggests that design directives obtained from mouse skin can be extended to design new prodrugs or select new drugs for delivery through human skin.

Synthesis and topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl prodrugs of a model phenolic drug: acetaminophen.

The synthesis, physicochemical characterization and flux of a homologous series of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of a model phenolic drug, acetaminophen (APAP), have been investigated. The most water soluble member of the series gave the highest transdermal delivery from isopropyl myristate (IPM) through hairless mouse skin. The flux of NANAOCAM prodrugs of APAP was accurately predicted by the Roberts-Sloan (RS) equation.

Topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of theophylline (ThH).

N(7)-(N-Alkyl-N-alkyloxycarbonyl) aminomethyl (NANAOCAM) prodrugs of theophylline (ThH) have been synthesized and characterized by their solubilities in isopropyl myristate (S(IPM)), solubilities in water (S(AQ)), partition coefficients between IPM and pH 4.0 buffer (K(IPM:4.0)) and by their ability to penetrate hairless mouse skin from IPM (J(MIPM)). The most lipid soluble and water soluble member, N-methyl-N-ethyloxy-carbonylaminomethyltheophylline, gave the highest flux through hairless mouse skin from IPM compared to ThH. The flux of NANAOCAM prodrugs of ThH can be accurately predicted by the Roberts-Sloan (RS) equation.

Application of the transformed Potts-Guy equation to in vivo human skin data.

Data developed by Wenkers and Lippold for the flux of 10 nonsteroidal anti-inflammatory drugs from light mineral oil (MO) through human skin in vivo has been analyzed using the transformed Potts-Guy equation. The analysis shows that the flux is dependent not only on the solubility in MO (S(MO)), but also on the solubility in acidic water (S(AQ)). This dependence of flux on S(AQ) shows that the previously reported dependence of flux on S(AQ) from in vitro experiments using hairless mouse skin is not an artifact of the in vitro experiments but is due to a characteristic of the skin barrier. Further inspection of the equations used by Wenkers and Lippold in their analyses of their data shows that the equations are variations of the transformed Potts-Guy equation.

Topical delivery of 5-fluorouracil (5-Fu) by 3-alkylcarbonyl-5-Fu prodrugs.

The solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SAQ) and the partition coefficients between IPM and pH 4.0 buffer (KIPM:AQ) have been measured for a series of 3-alkylcarbonyl-5-fluorouracil prodrugs (3-AC-5-FU). The 3-AC-5-FU prodrugs were all 100 times more soluble in IPM and the first two members of the series were also more soluble in pH 4.0 buffer than 5-FU. The abilities of the 3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (Ji) were also measured. The 3-propionyl derivative 3, which exhibited the highest SAQ in the series, gave the highest Ji value. The SIPM, SAQ and molecular weights (mw) of the 3-AC-5-FU series correctly predicted the rank order and very closely (0.10 log units) predicted the absolute values for logJi using the transformed Potts-Guy equation. Although the series of 3-AC-5-FU prodrugs was generally quite effective at increasing Ji (2-20 times), the best 3-AC-5-FU prodrug was not as effective as the best 1-alkylcarbonyl-5-FU prodrug (1-AC-5-FU) at increasing Ji and the ability of the 3-AC-5-FU prodrugs to increase the concentration of total 5-FU species in the skin was 2-5 times less than the 1-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain as the best prodrugs with which to enhance the topical delivery of 5-FU.

Prediction of transdermal flux of prodrugs of 5-fluorouracil, theophylline, and 6-mercaptopurine with a series/parallel model.

Multiple regression analysis of fluxes from suspensions in isopropyl myristate (J(M)) as a function of molecular weights (MW) and solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) were performed on a data set of 41 compounds (n = 41) comprising 39 prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP), in addition to 5-FU and Th, using four models. Two series/parallel models have been developed that allow an aqueous-only path in parallel with a lipid-only path and with a lipid-aqueous series path for the permeation of solutes through skin: log J(M) = log ¿1/[1/(aS(LIPID) 10(PhiMW)) + 1/(bS(AQ)/MW(1/2))] + cS(LIPID)10(PhiMW) + dS(AQ)/MW(1/2)¿ where a, b, c, and d are coefficients for flux through the lipid and aqueous portions of the series path, the lipid-only path, and the aqueous-only path, respectively, and Phi is the dependence of diffusivity in lipid on MW. In the first series/parallel model, S(LIPID) was predicted by S(IPM), and in the second, solvatochromic series/parallel model, S(LIPID) was predicted by S(IPM)(k MW + Omegai) where Omega(i) is the sum of the solvatochromic terms alpha, beta, pi, and R(2), and k is the coefficient for the dependence of partitioning on MW. Using the n = 41 solutions, the coefficients for the aqueous-only path were very small or not different from zero in the two series/parallel models, so only two-path series/parallel models were compared with the solvatochromic and transformed Potts-Guy models where a homogeneous barrier to permeation was assumed. For each model, one compound at a time was omitted from the data set and new parameter estimates were obtained for these 41-1 solutions and used to predict log J(M) for the omitted compound. The average errors of prediction of log J(M) (experimental log J(M) - predicted log J(M)) for the four models were 0.134 for the series/parallel (r(2) = 0.937), 0.127 for the solvatochromic series/parallel (r(2) = 0.967), 0.150 for the solvatochromic (r(2) = 0.950), and 0.134 log units for the transformed Potts-Guy model (r(2) = 0.944). Thus, the solvatochromic series/parallel model provides fit and predictive ability comparable to or slightly superior to previous models that assumed homogeneity of the diffusional barrier to flux in the rate-determining step, provides further theoretical support against the existence of a high capacity aqueous-only path, and provides further insight into the physicochemical properties that should be incorporated into solutes to optimize their flux. Using the solvatochromic series/parallel model, the parameter estimates for the n = 41 solution were used to calculate the flux of each compound through the two paths. For compounds with log partition coefficients (K(IPM:AQ)) of <0.8, permeation was mostly by the lipid-aqueous series path; for compounds with log K(IPM:AQ) >1.0, permeation was mostly by the lipid-only path; the lipid-aqueous series path exhibited the higher carrying capacity. (c) 2000 Wiley-Liss, Inc.

7-alkylcarbonyl and 7-alkyloxycarbonyl prodrugs of theophylline.

Five members (6-10) of an homologous series of 7-alkyloxycarbonyltheophylline (7-AOC-Th) and four members (2-5) of a homologous series of 7-alkylcarbonyltheophylline (7-AC-Th) prodrugs have been synthesized by known methods and characterized. All of the members in both series were much more soluble in isopropyl myristate (S(IMP)) (10-200 times) and in each series, at least one member was more soluble in pH 4.0 buffer (S(AQ)) than Th. However, in the 7-AC-Th series, only the acetyl member, 2, which exhibited about 90% of the S(AQ) of Th, was sufficiently stable to be evaluated - it gave four times the flux of Th/IPM (isopropyl myristate). In the 7-AOC-Th series, all the members were sufficiently stable to be evaluated but the member which exhibited the greatest S(AQ), 6 (methyloxycarbonyl), did not exhibit the greatest flux. Instead, 8 (propyloxycarbonyl), which exhibited the second greatest S(AQ) (about 80% of the S(AQ) of Th), but exhibited over ten times the S(IPM) of 6 gave the greatest flux - two times the flux of Th/IPM. Thus, good biphasic solubility was the best predictor of increased flux. All of the prodrugs delivered only Th through the mouse skin. Only 2/IPM actually delivered more Th into the skin than Th/IPM which correlated with its ability to increase the flux of Th through the skin.

Correlation of aqueous and lipid solubilities with flux for prodrugs of 5-fluorouracil, theophylline, and 6-mercaptopurine: A Potts-Guy approach.

The Potts and Guy equation that has been used to predict permeability coefficients for molecules being delivered from aqueous vehicles has been transformed to accommodate lipid vehicles that are less polar than skin, and polar vehicles that are less polar than water. Solubilities in pH 4.0 aqueous buffer (SAQ), solubilities in isopropyl myristate (SIPM), and molecular weights (MW) of prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP) have been regressed against their fluxes from suspensions in IPM (JM). Seven series (n = 39) of alkylcarbonyloxymethyl (ACOM), alkyloxycarbonyl (AOC), alkylcarbonyl (AC), and alkylaminocarbonyl (AAC) prodrugs were used to determine the best fit to the transformed Potts and Guy equation (eq 6): log JM = x + y log SIPM + (1 - y)log SAQ - z MW. The estimated values for x, y, and z were -0. 193, +0.525, and +0.00364, respectively, with r 2 = 0.945 for n = 39. Inclusion of a miscellaneous series comprised of the parent drugs and a branched alkyl chain prodrug gave an equally good fit only if 6-MP was excluded from the analysis. The best performer (largest JM) in each series was usually correctly identified. The values for x, y, and z were consistent with values obtained by Potts and Guy, but the inclusion of the (l - y)log SAQ term in eq 6 and the value for y, shows that water solubility is almost as important as lipid solubility in predicting flux. There were no significant changes in predicted log JM or xi for each series if their log JM or xi were calculated using y and z coefficients obtained for solutions to eq 6 from which the data for the series had been excluded. This suggests that the data from all the series is homogeneous. Data from Kasting, Smith, and Cooper for SIPM, SPG, and MW of unrelated molecules were regressed against their fluxes from propylene glycol (PG) using eq 7: log JM = x + y log SIPM + (1 - y) log SPG - z MW. The estimated values for x, y, and z were -1.673, +0.599, and +0.00595, respectively, with r 2 = 0.852 for n = 28. These values for x, y, and z are also consistent with those previously reported by Potts and Guy, and, together with the results for fluxes from IPM, show the general utility of the transformed Potts and Guy equation in predicting flux from vehicles other than water and in showing the importance of solubility in a polar solvent as well as a nonpolar solvent in predicting flux.

1-Alkylcarbonyloxymethyl prodrugs of 5-fluorouracil (5-FU): synthesis, physicochemical properties, and topical delivery of 5-FU.

1-Alkylcarbonyloxymethyl (1-ACOM) prodrugs of 5-fluorouracil (5-FU) have been synthesized and characterized by their solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SH2O), by their partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K) and by their abilities to deliver total 5-FU species into (Cs) and through (Ji) hairless mouse skin from an IPM vehicle. All of the prodrugs were much more lipophilic (SIPM) than 5-FU (> 60 times), and two members of the series (alkyl = C1 and C2, acetyl- and propionyloxymethyl) were also more soluble in water than 5-FU. The two more water-soluble members gave larger Ji values than the other members of the series, with C2 exhibiting the best biphasic solubility and the largest Ji value (16 times that of 5-FU). The ability of the 1-ACOM-5-FU prodrugs to deliver total 5-FU species into skin (Cs) was greater than the delivery of 5-FU by 5-FU, except for the last two members of series (alkyl = C7 and C9, octanoyl- and decanoyl-oxymethyl). However, the ratios of normalized Cs to Ji for the series was less than that exhibited by 5-FU, except for C7 and C9. Also, except for C9, significant amounts of intact prodrug as percentages of total 5-FU species were found in the receptor phases during the course of the diffusion cell experiments, ranging from 55% for C1 to 12% for C7.

A prodrug approach to increasing the oral potency of a phenolic drug. Part 2. Pharmacodynamics and preliminary bioavailability of an orally administered O-(imidomethyl) derivative of 17 beta-estradiol.

The O-saccharinylmethyl prodrug of 17 beta-estradiol was about nine times as potent, based on 50% effective dose (ED50) values, as 17 beta-estradiol when each was given as an oral dose to ovariectomized rats. Similarly, a significant lowering of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 24 h was observed when an ED50 dose of the prodrug was given but not when an equimolar dose of 17 beta-estradiol was given orally. However, when given intravenously, there was no difference in potency between the two drugs. In the bioavailability studies, a significantly longer half-life (approximately 5-7 times) for 17B-estradiol was observed when the prodrug was given orally than when 17 beta-estradiol was given orally or when the prodrug or 17 beta-estradiol were given intravenously. This result was consistent with an observed five-fold enhancement in the oral bioavailability of 17 beta-estradiol when the prodrug was given.

A prodrug approach to increasing the oral potency of a phenolic drug. 1. Synthesis, characterization, and stability of an O-(imidomethyl) derivative of 17 beta-estradiol.

An O-(saccharinylmethyl) prodrug was synthesized to improve the poor oral potency of the phenolic drug 17 beta-estradiol. This O-(imidomethyl) type of prodrug was designed to undergo chemical hydrolysis and to be a poor substrate for enzymatic hydrolysis. At 37 degrees C, it was found to exhibit half-lives of about 13 min in 50% methanol:pH 7.0 (v/v) phosphate buffer, about 3 min in rat plasma, about 15 min in human plasma, and about 50 min in 20% rat liver homogenate. Introduction of the enzyme poison tetraethyl pyrophosphate or the protein denaturant sodium fluoride into rat plasma had no significant effect on the half-life. Thus, the observed increased rate of hydrolysis in biological media is not due to enzymatic catalysis but to a nonspecific solventlike effect. The fact that the rate of hydrolysis in the methanol:buffer exhibited a first-order dependence on the hydroxide ion concentration and that the rate of hydrolysis increased with increasing methanol concentrations up to 70% supported an SN2 mechanism of hydrolysis for the prodrug. These results suggest that an O-(imidomethyl) type prodrug is insensitive to enzymatic catalysis of hydrolysis yet may hydrolyze quickly enough to release 17 beta-estradiol faster than 17 beta-estradiol is conjugated and excreted.

Structure of 3-acetyl-5-fluorouracil (5-FU): implication for its rearrangements during hydrolysis and upon heating.

Single-crystal X-ray diffraction data show that the 3-acetyl group in 1,3-diacetyl-5-FU (FU = fluorouracil) is perpendicular to the plane of the 5-FU ring, while the 1-acetyl group is coplanar with the ring. Analyses of 1H NMR and IR spectra provide evidence that the 1- and 3-acyl groups are in different electronic environments, which is consistent with the X-ray diffraction structure. 3-Acetyl-5-FU is thermally unstable, giving mainly 1-acetyl-5-FU (80%) and 5-FU (20%) upon heating. The hydrolysis of 3-acyl derivatives of 5-FU showed a biexponential relationship between in concentration and time which had not been previously observed. The behavior of 3-acetyl-5-FU during hydrolysis can be explained by postulating its initial rapid equilibrium with an intermediate, 2-acetyl-5-FU, which subsequently hydrolyzes to 5-FU or rearranges to 1-acetyl-5-FU, which hydrolyzes to 5-FU. The 2-acetyl intermediate was trapped by its reaction with formaldehyde. The formaldehyde adducts of the symmetrical 2-acetyl intermediate rearranged to yield equal amounts of 1- and 3-acetyloxymethyl-5-FU.

Effect of aminomethyl (N-Mannich base) derivatization on the ability of S6-acetyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin.

A series of 9-aminomethyl-S6-acetyloxymethyl-6-mercaptopurine (9-AM-6-AOM-6-MP) prodrugs have been synthesized and characterized, and their ability to deliver total 6-mercaptopurine (6-MP) through hairless mouse skin has been measured. The 9-AM-6-AOM-6-MP prodrugs are much more soluble in isopropyl myristate (IPM) than S6-acetyloxymethyl-6-MP (6-AOM-6-MP) itself or the corresponding 7-aminomethyl-6-MP (7-AM-6-MP) prodrugs. The 9-AM-6-AOM-6-MP prodrugs were all more effective (1.8-4 times) than 6-AOM-6-MP at delivering total 6-MP, except for the piperidylmethyl derivative which only gave a comparable rate of delivery. The 9-AM-6-AOM-6-MP prodrugs were also more effective (7-27 times) than the corresponding 7-AM-6-MP prodrugs at delivering 6-MP, except for the diethylaminomethyl derivative which only gave a comparable rate of delivery. In contrast to the 9-aminomethyl-S6-pivaloyloxymethyl-6-MP (9-AM-6-POM-6-MP) derivatives which generally delivered as much or more intact S6-pivaloyloxymethyl-6-MP (6-POM-6-MP) as 6-MP, the 9-AM-6-AOM-6-MP derivatives delivered mainly (80-95%) 6-MP from IPM. There was a direct correlation between log experimental permeability coefficients for delivery of total 6-MP (P sigma) and the calculated solubility parameter values for the 9-AM-6-AOM-6-MP prodrugs(delta j), with the P sigma generally decreasing as the value of delta j approached that of the vehicle, IPM.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation of 6-mercaptopurine (6-MP) with N-alkyl-N-alkoxycarbonylaminomethyl chlorides: S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP prodrug structure effect on the dermal delivery of 6-MP.

The S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP (6-CARB-6-MP) prodrugs 5-20 were synthesized from the reaction of 6-MP with N-alkyl-N-alkyoxycarbonylaminomethyl chlorides (4) in dimethyl sulfoxide in overall yields of 5-62%, depending on the N-alkyl and the alkoxy groups involved. The derivatives were fully characterized by spectral and microanalyses. The assignment of the substitution pattern as S6-alkyl was based on comparisons of the UV, 1H NMR and 13C NMR spectra with model compounds. A S6, 9-bis-alkyl derivative was obtained from the reaction of 2 equivalents of 4 with 6-MP but the product was unstable and decomposed on standing to a 9-alkyl derivative. The 6-CARB-6-MP prodrugs reverted to 6-MP in water by an SN1-type mechanism involving unimolecular charge separation in the transition state of the rate determining step. There was no effect of dermal enzymes on the rate of hydrolysis. The solubilities in isopropyl myristate (IPM) for all of the 6-CARB-6-MP prodrugs were significantly greater than the solubility of 6-MP in IPM but only one prodrug (5) was apparently even as soluble as 6-MP in water. Selected 6-CARB-6-MP prodrugs were examined in diffusion cell experiments. Only the N-methyl-N-methoxycarbonyl derivative 5 gave a steady-state rate of delivery of 6-MP from IPM that was significantly greater than the steady-state rate of delivery of 6-MP from 6-MP in IPM. All the other derivatives gave steady-state rates of delivery of 6-MP from IPM that were either not significantly different, or were significantly lower than the rate obtained from 6-MP in IPM. In all cases, the effect of the 6-CARB-6-MP:IPM suspensions on the permeability of the skin, as determined by the second application flux of theophylline:propylene glycol, was of the same magnitude as the effect of IPM alone.

Transdermal delivery of 5-fluorouracil through skin of hairless mice and humans in vitro: a comparison of the effect of formulations and a prodrug.

A 2% commercial solution formulation of 5-fluorouracil (5-FU) was significantly better at delivering 5-FU than either a 1% or 5% solution. Among single component suspension formulations the highest transdermal delivery was obtained from the vehicle in which 5-FU was least soluble, isopropyl myristate (IPM), while changes in the total suspended concentration of 5-FU in propyleneglycol (PG) had no significant effect on transdermal delivery by those suspensions. A prodrug of 5-FU/IPM was significantly better at delivering 5-FU than any of the formulations. The trends in relative rates of delivery of 5-FU by the formulations and the prodrug were the same in skin of hairless mice and humans. The mouse skin was about ten times more permeable than the human skin. Second application studies to assess skin damage caused by the formulations also showed the same trend in skin of hairless mice and humans: all of the formulations caused some damage.

Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: S6-acyloxymethyl-6-mercaptopurine prodrugs.

A homologous series of S6-acyloxymethyl-6-mercaptopurine (6-mono-6-MP) and two 9-acyloxymethyl-6-mercaptopurine (9-mono-6-MP) prodrugs have been synthesized and characterized. The ability of the 6-mono-6-MP prodrugs to deliver 6-mercaptopurine (6-MP) through hairless mouse skin from isopropyl myristate (IPM) and propylene glycol (PG) has been evaluated. There was a good correlation between the log experimental permeability coefficients from the diffusion data and calculated solubility parameters of the prodrugs. Although there was no statistical difference between the rates of delivery of 6-MP by the acetyl through valeryl 6-mono-6-MP prodrugs from IPM, the butyryl and valeryl prodrugs were significantly better at delivering 6-MP from PG. For a given solubility parameter value, the 6-mono-6-MP prodrugs were less soluble in water and IPM, and more soluble in PG than the previously studied S6,9-bisacyloxymethyl-6-MP (6,9-bis-6-MP) prodrugs. On the other hand, for a given solubility parameter, the 6,9-bis-6-MP prodrugs were generally more effective at delivering 6-MP from IPM and PG. The single 9-mono-6-MP prodrug that was evaluated was much less effective at delivering 6-MP than either the 6-mono- or 6,9-bis-6-MP prodrugs. Thus, it is much less important to mask the imidazole than the thionamide functional group in 6-MP to enhance the topical delivery of 6-MP using a prodrug approach.