Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D00206 (IPM)
1,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify the mechanism involved in the enhancement effect of enhancers on the intercellular penetration of large polar molecules, the skin penetration of fluorescein isothiocyanate (FITC)-dextrans (average molecular weight; 4400, 9400, and 69000 Da) and the lipid removal from the intercellular spaces by enhancers were studied using hairless rat skin. Pretreatment of hairless rat skin with enhancers such as n-octanol (20%), laurocapram (2%), isopropylmyristate (IPM, 20%), oleic acid (5%) and cineol (2%), which are water-immiscible, significantly enhanced the flux of FITC-dextrans, while pretreatment with water-miscible enhancers, i.e. dimethyl sulfoxide (DMSO, 5%) and N-methyl-2-pyrrolidone (NMP) did not increase the flux compared with the control. The penetration of FITC-dextrans was approximately size dependent. n-Octanol, laurocapram, IPM and oleic acid dramatically removed ceramides which are the intercellular lipids, whereas NMP and DMSO partly extracted the sphingolipids. A linear relationship was observed between the flux and removal of ceramides (p < 0.01), indicating that the removal of intercellular lipids would cause dramatic dilations between adherent cornified cells and enhance the penetration through the intercellular pathways. When the penetration of FITC-dextrans through Wistar rat skin was compared with that via hairless rat skin, the steady state flux of FITC-dextrans through Wistar rat skin pretreated with water-immiscible enhancers was 1.2- to 4.9-fold higher, suggesting that the penetration of large polar molecules through follicles may play at least some role in the percutaneous absorption.
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PMID:Percutaneous penetration of fluorescein isothiocyanate-dextrans and the mechanism for enhancement effect of enhancers on the intercellular penetration. 859 81

In order to relate barrier function to stratum corneum structure and the thermal transitions of corneum lipids, samples from hairless rat skin were investigated by using ESR and drug penetration techniques. The phase transition of stratum corneum lipids was estimated using a deeper probe (16-doxyl-stearic acid) inserted in the lipid bilayers and measuring the rotational correlation time, tau(c). Results of ESR study showed that stratum corneum lipids underwent thermal transitions at 39.3 +/- 1.6 degrees C and 63.6 +/- 2.6 degrees C roughly similar to the data obtained by differential scanning calorimetry measurements. Cholesterol oxidase treatment decreased the fluidity of the lipids at lower temperatures. The treatment of stratum corneum with laurocapram (1%) and isopropyl myristate (IPM, 2%) little changed both phase transition temperatures, although the treatment highly increased the molecular motion of the lipids. The flux (J(s)) of lipophilic drugs (beta-estradiol, indomethacin and betahistine) through the skin was enhanced with increasing temperatures, with an increase in the diffusion constant within skin and a decrease in the lag time. There was a good relationship between log J(s) or log permeability coefficient (K(p)) and 1/tau(c) in the temperature range of 45 to 64 degrees C. The calculated activation energy (delta E) for diffusion of these drugs across skin was 17-40 kcal/mol. Judging from our data, stratum corneum lipids of rat probably exist as the gel, crystalline state below 39 degrees C, the mesomorphic state between 39 and 64 degrees C and the fluid, liquid-crystalline state at temperatures of 64 degrees C or above. These results are in line with the permeability of these lipophilic drugs through the intercellular lipids disordered is highly increased.
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PMID:Phase transitions of rat stratum corneum lipids by an electron paramagnetic resonance study and relationship of phase states to drug penetration. 865 57

Cutaneous disposition of topically applied flurbiprofen (FP) was evaluated using a new in situ experimental model in hairless rats. A disk-shaped agar gel (3.85 cm in diameter and 0.5 cm in thickness) was subcutaneously implanted in the abdominal region of rats as a drug receptor, and a drug donor cell was subsequently placed above this agar gel. No significant pharmacokinetic modification of FP was observed as a result of this experimental procedure. A bolus injection and a constant intravenous infusion of FP were applied to the rats, followed by an analysis of FP levels in the plasma and agar gels. Using these results, the clearance rate of FP from the systemic circulation to the gel could be calculated. FP (1% gel formulation, 1.0 g/3.14 cm(2)) was then topically applied to the skin of these rats. From these experiments, the amount of FP that migrated from the formulation to the systemic circulation and the amount of FP that migrated directly to the agar gel across the skin, over 10 h, were separately evaluated to be 235.4 and 2.0 microg, respectively. Thus, most of the FP was absorbed into the systemic circulation. The effect of endogeneous vasoactive compounds and penetration enhancers on the FP disposition within skin was also determined. Epinephrine and bradykinin were used as vasoactive compounds that were entrapped in agar gel, and an isopropyl myristate system (IPM system) and a l-menthol-ethanol-glycerin-water system (MEGW system) were used as enhancers in the formulation. Epinephrine enhanced the direct delivery of FP into the agar gel to more than ten times its former level, in spite of the fact that it had no effect on systemic delivery. Bradykinin strengthened systemic delivery slightly, without changing the quantity of FP in the gel. IPM increased only the systemic delivery of FP, as was the case with bradykinin, whereas the MEGW system markedly increased both the blood concentration and the quantity of FP in the gel (13 and 200 times, respectively). This technique has proven to be an effective tool for the quantitative evaluation of cutaneous disposition of a topically applied drug.
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PMID:Analysis of skin disposition of flurbiprofen after topical application in hairless rats. 1051 51

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.
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PMID:Topical delivery of 5-fluorouracil (5-Fu) by 3-alkylcarbonyl-5-Fu prodrugs. 1129 49

The solubilities in isopropyl myristate (S(IPM)) and pH 4.0 buffer (S(AQ)) and the partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)) have been measured for a series of 1,3-bisalkylcarbonyl-5-fluorouracil prodrugs (1,3-AC-5-FU). The 1,3-AC-5-FU prodrugs were each over 500 times more soluble in IPM, but all members of the series, whose solubilities could be estimated, were much less soluble in pH 4.0 buffer than 5-FU. The abilities of the 1,3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (J(i)) were also measured. The 1,3-diacetyl derivative 2, which exhibited the highest S(AQ) in the series, gave the highest J(i) value. Although the series of 1,3-AC-5-FU prodrugs was generally effective at increasing J(i) (three to ten times), the best 1,3-AC-5-FU prodrug was not as effective as the best 1- or 3-alkylcarbonyl-5-FU prodrug (1- or 3-AC-5-FU) at increasing J(i) and their ability to increase the concentration of total 5-FU species in the skin was generally less than that of the 1-AC-5-FU prodrugs, but greater than that of the 3-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain the best prodrugs with which to enhance the topical delivery of 5-FU.
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PMID:Topical delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs. 1171 12

The 3-alkylcarbonyloxymethyl-5-fluorouracil (3-ACOM-5-FU) prodrugs have been characterized by their solubilities in isopropyl myristate (S(IPM)) and partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)). Estimated S(AQ) values have been obtained from S(AQ) = S(IPM)/K(IPM:AQ.) The abilities of the prodrugs to deliver total 5-FU species from IPM suspensions through hairless mouse skin (J(i)) have been evaluated in diffusion cell experiments. All of the prodrugs were much more soluble in IPM than 5-FU, and the propionyloxymethyl (C2) member of the series was almost twice as soluble in pH 4.0 buffer. Except for the acetyloxymethyl (C1) member of the series, the 3-ACOM-5-FU prodrugs exhibited greater S(IPM) and S(AQ) values than the corresponding 1-alkylcarbonyloxymethyl (1-ACOM-5-FU) prodrugs. The 3-ACOM-5-FU prodrugs that exhibited greater S(IPM) and S(AQ) values than the 1-ACOM-5-FU prodrugs also exhibited greater J(i) values, except for the C2 member. The C2 member also gave the largest error in predicting J(i) using the transformed Potts-Guy equation. All of the 3-ACOM-5-FU prodrugs delivered more 5-FU as a percentage of J(i) than the 1-ACOM-5-FU prodrugs but were not more effective as a series at targeting dermal as opposed to transdermal delivery.
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PMID:Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyloxymethyl-5-FU prodrugs. 1271 22

It has been shown for homologous series of prodrugs that those members who were the more water soluble ones gave the greatest enhancement in topical delivery of the parent drug and not the more lipophilic ones. However, until recently models for topical delivery and equations to predict topical delivery focused only on lipid solubility (S(LIPID)) or partition coefficient (K(OCT:AQ)) and molecular volume (or molecular weight, MW) as parameters. Now several equations (transformed Potts-Guy or Series/Parallel) have been developed which include aqueous solubility (SAQ) as a parameter for predicting flux through skin. Experimental fluxes, solubilities, and MW from seven series of prodrugs have been fit to the transformed Potts-Guy equation to give coefficients for log solubility in isopropyl myristate (log SIPM) and log solubility in water (log SAQ) (0.53 and 0.47, respectively) which show, for parent drugs delivered by prodrugs from IPM in vitro through hairless mouse skin, that water solubility is almost as important as lipid solubility. When the transformed Potts-Guy equation was fit to data for the delivery of NSAID from mineral oil (MO) in vivo through human skin, the coefficients were 0.72 log SMO and 0.28 log SAQ. When the transformed Potts-Guy equation was fit to data for the delivery of their parent drugs by three series of prodrugs from water in vitro through hairless mouse skin the coefficients were 0.66 log S(IPM) and 0.34 log SAQ. Numerous recent examples are also given where more water-soluble members of homologous series of prodrugs give higher flux values from water vehicles in vitro through human skin than the more lipid soluble ones.
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PMID:Designing for topical delivery: prodrugs can make the difference. 1293 91

Synthesis, characterization and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of substituted phenols, theophylline (Th) and 6-mercaptopurine (6MP) were carried out. The mechanism of hydrolysis was further investigated by synthesis, characterization and hydrolysis of N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of phenols. The hydrolysis follows pseudounimolecular first order kinetics and operates by way of an S(N)1-type mechanism. Topical delivery of selected derivatives of acetaminophen (APAP), Th and 6MP was examined in in vitro diffusion cell experiments from IPM across hairless mice skins. The prodrug of APAP and 6MP increased permeation across the skin by about 2- and 4-fold, respectively, compared to the parent drug. NANAOCAM promoieties can act as novel prodrug derivatives of phenol, imide and thiol containing drugs for enhancing topical absorption.
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PMID:Synthesis, hydrolyses and dermal delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide and thiol containing drugs. 1661 88

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.
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PMID:Topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of theophylline (ThH). 1706 62

Synthesis and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) and N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of carboxylic acid containing drugs were carried out. The hydrolysis follows a S(N)1 type mechanism and is dependent on the nucleofugacity of the leaving group. Topical delivery of the NANAOCAM derivative of naproxen from IPM across hairless mice skin was examined in in vitro diffusion cell experiments. The prodrug was 4.5-fold less lipid soluble, 2.4-fold less water soluble and 3.6-fold less permeable than the parent drug.
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PMID:N-Alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of carboxylic acid containing drugs. 1719 86


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