Influence of skin thickness on the in vitro permeabilities of drugs through Sprague-Dawley rat or Yucatan micropig skin

The purpose of this study was to clarify the influence of skin thickness on the in vitro permeabilities of 3 model drugs with different physicochemical properties (nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP)) through Sprague-Dawley rat (rat) or Yucatan micropig (YMP) skin. Intact, dermis-split, stratum corneum-stripped or stratum corneum-stripped and dermis-split rat or YMP skin (rat skin thickness: approximately 0.4, 0.9 or 1.2 mm; YMP skin thickness: approximately 0.4, 0.9, 1.8 or 2.8 mm) were set in Franz-type diffusion cells to determine the permeation rate, lag time and resistance ratio of the viable epidermis and dermis against whole skin (R(ved)/R(tot)) of the drugs. The YMP skin permeabilities of the drugs decreased with an increase in the skin thickness, and significant differences were observed in the permeation rates and lag times between intact and dermis-split (0.4 mm) YMP skins. The decreases in the permeabilities of the drugs through the YMP skin were larger than those through the rat skin. The influence of resistances of ISDN and FP through the dermis-split rat or YMP skin was greater at 0.9 mm skin thickness than 0.4 mm skin thickness. The R(ved)/R(tot) values for the YMP skins were relatively large for lipophilic drugs (ISDN and FP), and these ratios increased with an increase in the dermis thickness. These results suggest that in vitro skin permeation studies must be done using dermis-split (0.4 mm) skin with the thinnest dermis for predicting in vivo human percutaneous absorption rate.     

Effect of Direction (Epidermis-To-Dermis and Dermis-To-Epidermis) on the Permeation of Several Chemical Compounds through Full-Thickness Skin and Stripped Skin

Purpose

Compound permeation through stratum corneum-stripped skin is generally greater than that through full-thickness skin. In addition, epidermis-to-dermis permeation profile should be the same as dermis-to-epidermis permeation profile. However, stripped skin permeability of some compounds was lower than full-thickness skin permeability and different permeabilities were found for some compounds between the two directions of skin permeation. The reasons for these findings were investigated in this study.

Methods

Full-thickness or stripped hairless rat skin was set in a Franz-type diffusion cell, and a solution of compound was applied on the epidermis or dermis side to determine the in vitro skin permeability.

Results

Although the stripped skin permeability of pentyl paraben (PeP) with extremely high logK _o/w was lower than full-thickness skin permeabilities, the addition of 3% ethanol resulted in the expected permeation order. Epidermis-to-dermis permeation of PeP through full-thickness skin was higher than dermis-to-epidermis permeation. Epidermis-to-dermis permeations of fluorescein isothiocyanate dextran (FD-4) and isosorbide 5-mononitrate with negative logK _o/w were also higher than those in the opposite direction.

Conclusions

Morphological observation of skin after FD-4 permeation suggested that a conically shaped trans-follicular permeation pathway model could be advocated to explain the difference between the epidermis-to-dermis permeation and that in the opposite direction.     

硝酸酯类药物不同途径给药后的药动学比较

目的 :评价 5 单硝酸异山梨酯 (5 ISMN)片剂和注射剂及硝酸异山梨酯 (ISDN)注射剂在中国健康受试者中的药动学特征。方法 :18名男性健康受试者采用自身对照交叉给药的方式 ,单剂量口服5 ISMN片剂 2 0mg或静脉滴注 (静滴 ) 5 ISMN注射剂 (5mg·h- 1,维持 4h)或ISDN注射剂 (5mg·h- 1,维持 4h) ,采用气相色谱法测定血药浓度。结果 :18名受试者口服 5 ISMN片剂和静滴 5 ISMN注射剂后的药动学参数为 :Tmax 分别为 (0 .7±s 0 .6 ) ,(4 .1± 0 .7)h ;Cmax分别为 (389± 86 ) ,(2 83± 5 9) μg·L- 1;AUC0 ∞ 分别为 (32 6 6± 6 2 4 ) ,(3179± 76 9) μg·h·L- 1。静滴ISDN注射剂后IS DN ,2 单硝酸异山梨酯 (2 ISMN )和 5 ISMN的Cmax分别为 (18± 7) ,(5 9± 4 ) ,(2 0 9± 5 0 ) μg·L- 1;AUC0 t分别为 (85± 2 8) ,(380± 5 9) ,(1384± 4 2 7)μg·h·L- 1;T1/2 分别为 (1.0 0± 0 .2 0 ) ,(2 .6±0 .8) ,(6 .1± 0 .9)h。结论 :5 ISMN片剂与注射剂相比 ,两者的AUC等效 ,但片剂的达峰时间明显快于注射剂。ISDN注射剂给药后能较快达到稳态浓度 ,而且迅速代谢成活性代谢产物。     

Inhibition of angiogenesis, tumour growth and metastasis by the NO-releasing vasodilators, isosorbide mononitrate and dinitrate.

1. The effect of the nitric oxide (NO)-producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice. 2. Isosorbide 5-mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose-dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of alpha-thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside which generates NO non-enzymatically. 3. Mice, implanted intramuscularly with LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a reduction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN. 4. Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial cells and to cultures of LLC cells had no effect on their growth characteristics. 5. These results indicate that ISMN and ISDN inhibit angiogenesis and tumor growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.     

Effects of pretreatment of needle puncture and sandpaper abrasion on the in vitro skin permeation of fluorescein isothiocyanate (FITC)-dextran

Microneedle systems have gained attention as having many advantages over transdermal patches and hypodermic needles. The procedure provides adequate skin permeation rates without pain or severe infection. To obtain information for designing a microneedle system, macroneedles were used instead of microneedles to investigate the effects of pretreatment of needle puncture in the skin barrier stratum corneum on in vitro skin permeation of fluorescein isothiocyanate (FITC)-dextrans (4.3, 9.6 and 42.0 kDa) (FD-4, FD-10 and FD-40). The effect of sandpaper abrasion was also investigated for comparison. Both pretreatments on the skin barrier significantly increased the skin permeation of FDs. Lactate dehydrogenase (LDH) leaching was measured after pretreatment of macroneedle and sandpaper abrasion on the skin to evaluate the skin damage by these pretreatment methods. Lower leaching of LDH was observed after macroneedle puncture than after sandpaper abrasion. Next, a parallel permeation-resistance model of the skin barrier was established. Skin permeation of FD-10 was predicted by the model as a function of the number of pores in the skin barrier. Our results suggest that needle puncture may provide a safe, efficient and controllable alternative for increasing transdermal drug delivery.     

Nitro compounds (isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate) on the femoral vein and femoral artery

In organ bath studies, the selectivity of isolated femoral vein and artery of rabbit to isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), major metabolite of ISDN, and glyceryl trinitrate (GTN) was compared. The femoral vein and artery contracted by norepinephrine were relaxed by all the nitro compounds dose-dependently. Potency order was GTN greater than ISDN greater than ISMN. The maximum inhibitory responses to the nitrocompounds and their pIC50 values (negative logarithms of doses to induce the 50% response) were greater in the femoral vein than in the femoral artery. For ISMN a 3 times greater sensitivity of femoral vein than of femoral artery was found.     

Effects of nitro compounds, isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate on Ca-uptake into Ca-stores and Ca-release from Ca-stores in rabbit isolated femoral veins and femoral arteries

In organ bath studies, effects of isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), a major metabolite of ISDN, and glyceryl trinitrate (GTN) on Ca-uptake into Ca-stores and Ca-release from Ca-stores were tested in the rabbit isolated femoral veins and femoral arteries. ISDN (10(-4) M) and GTN (10(-4) M) inhibited Ca-uptake in the femoral veins but not in the femoral arteries. The selectivity to the femoral veins was not observed in ISMN (10(-3) M) and GTN (3 X 10(-6) M). All the nitro compounds inhibited Ca-release from Ca-stores more effectively in the femoral veins than in the femoral arteries. The present results may explain the selectivity of the nitro compounds to the femoral veins.     

Transdermal delivery of penetrants with differing lipophilicities using O-acylmenthol derivatives as penetration enhancers

To develop more effective compounds as penetration enhancers, O-acylmenthol derivatives were synthesized by l-menthol and saturated fatty acid, O-ethylmenthol (MET), was also synthesized as a reference compound. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), indomethacin (IM), which were selected based on their lipophilicity represented by log K_O/W, was tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. Only 2-isopropyl-5-methylcyclohexyl tetradecanoate (C14 alkyl chain) had promoting effects on the percutaneous permeation of 5-FU; 2-isopropyl-5-methylcyclohexyl hexanoate (C6 alkyl chain), which increased the permeation coefficient (P) 1.91-fold, had the highest permeation for ISDN; in the case of LD, the highest increase in P was observed with 2-isopropyl-5-methylcyclohexyl heptanoate (C7 alkyl chain), which increased the P by 1.58-fold; MET, which increased the P by 2.02-fold, provided the best enhancement for KP; 2-isopropyl-5-methylcyclohexyl heptanoate (C7 alkyl chain) produced the highest increase in P, 3.70-fold for IM. These results suggest that some newly designed percutaneous absorption enhancers have the potential to enhance drugs with different lipophilicities. A chain length of C6–C10 seemed to be favorable for lipophilic drugs, while C14 was the most effective enhancer for hydrophilic drug (5-FU).     

Pretreatment effects of moxibustion on the skin permeation of FITC-dextran

This study was conducted to evaluate the pretreatment effects of different in vivo moxibustion on the permeation of a model high molecular compound, FITC-dextran, with a mean molecular weight of 4 kDa (FD-4), through excised hairless rat skin. Direct or indirect moxibustion (0.10 g moxa) was pretreated consecutively 4 times every 5 min on the abdomen of hairless rats, and the permeation of FD-4 was determined through the excised skin over 8h from 30 min after starting the first moxibustion. This consecutive moxibustion pretreatment showed a significant increase in the skin temperature as well as skin permeation of FD-4 compared with the control group (no moxibustion pretreatment). Quantitative parameters showed an increase in skin temperature and skin permeation: the area under the skin temperature over control temperature-time curve during one burning cycle (5.0 min) (AUCtemp) or the maximum skin temperature during moxibustion (Tmax) and the cumulative amount of FD-4 permeated through skin over 8h (Q8) or steady-state flux were increased by moxibustion pretreatment. Then, the effect of pedestal thickness (distance from the moxa cylinder and skin surface), shape of the moxa cylinder (5mm diameter, 13 mm height or 9 mm diameter, 7 mm height), burning materials (moxa or aromatic incense), pedestal component (paper, potato or ginger) and moxibustion pretreatment method (direct or indirect moxibustion) was evaluated on the AUCtemp or Tmax and Q8 or flux. The amount of protein leached from the skin surface was also determined as an inflammatory index by this moxibustion pretreatment. When the skin temperature was increased to 60 degrees C, the Q8 or flux as well as the amount of protein leached were markedly increased. When the skin temperature was controlled to 42 to 45 degrees C by an adequate selection of pedestal thickness, shape of the moxa cylinder, burning materials, pedestal component and moxibustion pretreatment method, on the other hand, protein leaching remained unaltered, but the Q8 or flux significantly increased with the Tmax. This study thus provides credible evidence that moxibustion pretreatment increases the skin permeation of high molecular compounds.     

Absorption of Isosorbide Dinitrate after Administration as Spray,Ointment and Microemulsion Patch. An In-vitro Study Using the Isolated Perfused Bovine Udder

The isolated perfused bovine udder is an in-vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in-vitro model, the percutaneous absorption and metabolism of isosorbide dinitrate (ISDN) was studied. The organ was perfused with gassed Tyrode solution for up to 6 h. A region of udder skin was treated topically with 60 mg ISDN as a spray, 60 mg ISDN as an ointment and with 120mg ISDN as a microemulsion patch of 30 cm². Spray and ointment were applied onto a skin region of 400 cm². The concentrations of ISDN and its metabolites isosorbide-2-mononitrate and isosorbide-5-mononitrate were measured in perfusate fractions by capillary column gas-liquid chromatography with electron capture detection. Following topical administration of the different formulations, ISDN as well as its metabolites were detected in the perfusate fractions, thus demonstrating that ISDN is metabolized by the udder skin in-vitro. A maximum amount of ISDN was absorbed after administration as a spray followed by ointment and microemulsion (5, 2·5 and 1·8 μmol total organic nitrate, respectively). In contrast, the ISDN flux per cm² skin was significantly higher after administration of the microemulsion (64·4 pmol cm^?2 min^?1 for the microemulsion compared with 21·9 and 10·2 pmol cm^?2 min^?1 for spray and ointment).     

Transdermal delivery of fluorescein isothiocyanate-dextrans using the combination of microneedles and low-frequency sonophoresis

This study aimed to evaluate the patient-friendly methods that are used in the delivery of hydrophilic macromolecules into deep skin layers, in particular, the combination of microneedles patch (MNs patch) and low-frequency sonophoresis (SN). The hydrophilic macromolecule drug fluorescein isothiocyanate (FITC)-dextrans (FD-4: MW 4.4 kDa) was used as the model drug in our experimental design. In this study, excised porcine skin was used to investigate and optimize the key parameters that determine effective MNs- and SN-facilitated FD-4 delivery. In vitro skin permeation experiments revealed that the combination of MNs patch with SN had a superior enhancing effect of skin permeation for FD-4 compared to MNs alone, SN alone or untreated skin, respectively. The optimal parameters for the combination of MNs and SN included the following: 10 N insertion force of MNs, 4 W/cm² SN intensity, 6 mm radiation diameter of the SN probe, 2 min application time, and the continuous mode duty cycle of SN. In addition, vertical sections of skin, clearly observed under a confocal microscope, confirmed that the combination of MNs and SN enhanced permeation of FD-4 into the deep skin layers. These studies suggest that the combination of MNs and SN techniques could have great potential in the delivery of hydrophilic macromolecules into deep skin.     

Prediction of skin permeability of drugs: comparison of human and hairless rat skin.

Relationships between skin permeability and physicochemical properties of drugs were examined to establish a predictive method for the steady-state permeation rate of drugs through human skin. Human skin permeation properties fell into two categories: one in which the permeability coefficient is correlated to the partition coefficient, revealed with lipophilic drugs; and the other in which the permeability coefficients are almost constant, shown with hydrophilic drugs. The stratum corneum, the main barrier in skin, could be considered as a membrane with two parallel permeation pathways: lipid and pore pathways, and an equation for predicting the steady-state permeation rate of drugs was derived. The skin permeabilities of drugs for man were compared with those for hairless rat. The species difference in skin permeability found was suggested to be due to the difference in skin permeation pathways, since lipid content and water uptake of the stratum corneum varied between human and hairless rat skin.     

The enhancing effect of a triethanolamine-ethanol-isopropyl myristate mixed system on the skin permeation of acidic drugs

The effect of a TEI enhancer mixed system consisting of triethanolamine (T), ethanol (E) and isopropyl myristate (IPM) on the skin permeation of acidic, basic and neutral drugs were evaluated in vitro using excised hairless rat skin. The binary enhancer system consisting of IPM and ethanol (El) produced marked improvement on the penetration of all the drugs tested. When T was added to the EI system, a greater enhancing effect was found only on acidic drugs with a carboxyl group, compared with the flux in the EI system. On addition of another amine to the EI system, instead of T, mefenamic acid (MA), which exhibited the highest enhancing effect of the model drugs, showed an approximately 14-180 times greater flux than when delivered by the EI system. On simultaneous application of isosorbide dinitrate (ISDN) with MA in the TEI system, the flux of MA increased on increasing the T concentration in the TEI system, while, the flux of ISDN, a neutral drug, was unaffected by the T concentration. Application of MA in the EI system after pretreatment of the TEI system showed that the residual amount of T in the skin plays an important role in the skin permeation of MA. Furthermore, at a fixed concentration of MA, the flux of MA increased on increasing the T concentration in the TEI system, while the flux of E remained unchanged. Finally, the infrared spectrum of MA with amine in the E solution indicated that the carboxyl group of MA was ionized. These results demonstrated that the formation of an ion pair between MA and T, but not the effect of T on the skin, may be responsible for the enhanced skin permeation of MA using the TEI system.     

An Application of the Hydrodynamic Pore Theory to Percutaneous Absorption of Drugs

Skin permeability of drugs was evaluated based on the hydrodynamic pore theory. Four polar solutes were used, with differing molecular sizes—ethylene glycol, 1,3-butylene glycol, antipyrine and sucrose—and isosorbide dinitrate was also selected as a lipophilic drug. The skin permeations of solvent (D₂O) and one of these drugs were measured simultaneously under various osmotic pressures to calculate the reflection coefficient. The clearance of isosorbide dinitrate was independent of the solvent flux, whereas a linear relationship was obtained between the solvent flux and the clearance of each hydrophilic drug except for sucrose. The reflection coefficient of the hydrophilic drugs increased with increasing molecular radius. These results suggest that the convective flow contributes significantly to the total skin permeability of hydrophilic drugs and that the extent of contribution decreases with increasing molecular size of the drugs. The pore radius of the skin barrier could be estimated from the reflection coefficient of the hydrophilic drugs and the resulting value was compared with that for the other absorption sites, jejunum, rectum, and nose. The apparent water influx was also compared to assess the volume occupied by the pores. The pore radius and apparent influx of skin were lower than those for the other absorption sites, which is apparently one reason for low skin permeability of drugs, especially hydrophilic drugs.     

Comparison of the percutaneous absorption of hydrophilic and lipophilic compounds in shed snake skin and human skin

The in vitro transdermal permeation of eight hydrophilic drugs (antipyrine, L-dopa, dopamine hydrochloride, diclofenac sodium, 5-fluorouracil, isoprenaline hydrochloride, nicorandil and morphine hydrochloride) and eight lipophilic drugs (aminopyrine, cyclobarbital, ibuprofen, indomethacin, isosorbide dinitrate, flurbiprofen, ketoprofen and lignocaine) was determined using shed snake skin of Elaphae obsoleta and human skin. The permeation parameters and physiological characteristics of the skin, e.g. the water and lipid content, and the thickness of shed snake skin and human skin were evaluated and compared. In shed snake skin, the permeability coefficients (P) of lipophilic drugs were in the same range as those through the human skin (0.9 to 1.8-times); whereas those of hydrophilic drugs were remarkably lower (3.3 to 6.1-times). The thickness and lipid content of shed snake skin and human stratum corneum were not significantly different (P > 0.05), whereas the water content of shed snake skin was significantly lower than that of human stratum corneum (P < 0.05). The lower permeability of shed snake skin for hydrophilic compounds might be caused by the lower porosity of skin strata. The results suggested a potential use of shed snake skin as barrier membrane for lipophilic compounds percutaneous absorption studies in vitro.     

Variation assessment for in vitro permeabilities through Yucatan micropig skin

The purpose of this study was to evaluate the variations in the in vitro Yucatan micropig (YMP) skin permeabilities of drugs and to clarify whether YMP skin can be used to predict human skin permeability. In vitro permeation studies of the three model drugs, nicorandil, isosorbide dinitrate and flurbiprofen, through YMP skin were performed using Franz-type diffusion cells. The permeation rates of the three model drugs were determined, and their variations were evaluated. The inter-individual variations in YMP skin permeability for the three model drugs were smaller than that in human skin permeability, and the permeation rates of the three model drugs through the YMP skin were approximately half that through human skin. In addition, the intra-individual variations in YMP skin permeability for nicorandil and flurbiprofen were much smaller than the inter-individual variations in YMP skin. The inter- and intra-regional variations in YMP skin permeability were very small. The markedly smaller variation in the permeability through YMP skin as compared with that through human skin indicated that in vitro permeation studies using YMP skin would be particularly useful for evaluating differences in the skin permeability of the three model drugs as well as for predicting human skin permeability.     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Pharmacology of isosorbide dinitrate after transdermal application

Different organic nitrates exhibit markedly different in vitro partition coefficients, P. The lipophilic character, of which P is a measure, is the most important physico-chemical property which influences the penetration of nitrate molecules through the skin. It follows that there are several possibilities for developing formulations in which the diffusion of the molecules through the layers of the epidermis is furthered. A transdermal spray of isosorbide dinitrate (ISDN, TD Spray Iso Mack) was administered to volunteers and blood concentrations of the nitrate were measured. The results demonstrate that therapeutically effective amounts of the nitrate do in fact penetrate through the various levels of the skin. In addition pharmacokinetic measurements confirm that ISDN penetrates from the sprayed on film into the surface of the skin within 20 min and is then slowly released from the epidermis into the capillaries of the corium. An advantage of the administration of ISDN through the skin lies in the avoidance of the rapid metabolism of the drug which takes place during its first passage through the liver (first-pass effect). The protracted efficacy of the transdermal spray in the treatment of patients with coronary disease is, therefore, due to the unchanged ISDN and not, as with oral treatment, to pharmacologically active metabolites.     

Absorption and excretion of isosorbide dinitrate and isosorbide-2-mononitrate in dogs

In a crossover design four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.     

The effect of water solubility of solutes on their flux through human skin in vitro: a prodrug database integrated into the extended Flynn database

To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.