Anticipating Chemical Absorption from Complex Chemical Mixtures Jim E. Riviere, DVM, PhD, DSc hon Center for Chemical T.

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How do medications and chemicals connect with skin?. Skin is frequently touted just like the body\'s essential hindrance to assimilation of harmful chemicalsyetSkin is regularly a favored course of medication organization (e.g. transdermal nicotine, scopolamine patches). Natural Functions of Skin include:Physical Barrier: stratum corneumThermoregulation: hair, sweat organs, blood stream shuntsMechanical bolster: collagen,
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Anticipating Chemical Absorption from Complex Chemical Mixtures Jim E. Riviere, DVM, PhD, DSc ( hon ) Center for Chemical Toxicology Research and Pharmacokinetics North Carolina State University Work upheld by NIH OH-07555, OH-03669; AFOSR FA 9550-04-1-0376, Novartis

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How do medications and chemicals connect with skin? Skin is frequently touted similar to the body\'s essential obstruction to ingestion of poisonous chemicals yet Skin is regularly a favored course of medication organization (e.g. transdermal nicotine, scopolamine patches)

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Skin Biological Functions of Skin include: Physical Barrier: stratum corneum Thermoregulation: hair, sweat organs, blood stream shunts Mechanical support: collagen, water Neurosensory gathering: Immunological reaction: keratinocytes, Langerhans Cells

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Anatomical Considerations Primary boundary to medication retention is the stratum corneum Composed of dead keratinocytes installed in a lipid grid, through which most medications are assimilated. Lipid lattice discharged by cells in lower layer Basal layer contains suitable keratinocytes which relocate to surface and are eventually shed.

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Skin : PORTAL of passage and TARGET for lethality { IL-8, TNF  , Others SYSTEMIC EFFECT

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Diffusion is the essential main impetus moving chemicals over the stratum corneum. Rate of exchange is needy upon Fick\'s Law where: D = Diffusivity, d = Distance Pc = Partition Coefficient, SA=Surface Area, C = Concentration Rate consistent: penetrability coefficient Kp dC H/dt = ( D Pc Sa/d ) C H K P =D Pc/d Pharmacokinetics: d X/d t/Sa = (K p ) (X) Rate of medication development is relative to the measurements (X).

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Importance of Lipid Biochemistry/Biophysics Removal of stratum corneum builds assimilation Intercellular lipids are the essential pathway for medication ingestion Consist fundamentally of ceramides, sterols, and other nonpartisan lipids Exist in a fluid crystalline framework, the ease of which is identified with penetrability of hydrophilic medications Temperature, hydration and substance infiltration enhancers increment ease and porousness

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Major push of research is on the dermal retention of medications and chemicals crosswise over skin. - Developed a suite of novel in silico, in vitro and in vivo creature models - Current concentration is on anticipating blend communications in light of physical synthetic properties, and concentrate dermal harmfulness and assimilation of nanomaterial crosswise over skin - Need is for plan of transdermal and topical pharmaceutics and for hazard appraisal after human concoction introduction to natural and word related chemicals

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Suite of Research Models In silico: M athematical Models In Vitro: Membrane Coated Fiber Array Silastic Diffusion Cells Porcine and human skin dissemination cells Keratinocyte cell culture (Human and Porcine) Isolated Perfused Porcine Skin Flap (IPPSF) In Vivo: Pigs

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Porcine skin is fundamentally the same as human skin : Structure Function Lipid piece Human stomach skin, 150X Pig stomach skin, 150X

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Two Novel Approaches to Predict Dermal Absorption of Complex (> 2 Components) Mixtures Mixture consider (MF) consolidated into a QSAR/QSPR demonstrate Diffusion cell tests Isolated Perfused Porcine Skin Flap (IPPSF) Membrane Coated Fiber (MCF) cluster Present information as "Verification of Concept" Time licenses concentrate on highlights and results as it were.

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QSPR of dermal assimilation has a long history including work by Potts, Hansch, and Abraham Attempt to associate porousness through skin (Kp) to log K oct/water or physical synthetic properties Extension of solvation vitality (LFER) connections First far reaching use in skin was by Potts and Guy Log K p = 0.71 log K o/w – 0.0061 MW – 6.3 Log K p = 0.03MV – 1.7  2 H – 3.9  2 H – 4.8 Log K p = c + rR + s  + a + b + vV Specific model chose is not significant as is approach for fusing blend impact into model.

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Experimental Design Dependent variable is log Kp. Subsequent to fitting LFER model to information free of blend, a Mixture Factor (MF) is computed in light of a physical concoction property of the blend segments {refractive list, polarizability, log (1/Henry Constant)} weighted by their percent structure in the blend. Chosen by inspecting relationship amongst MF and LFER deposits through change in R 2 , Q 2 and F. Will exhibit move through dissemination cell investigation of 12 mixes dosed in 24 blends for an aggregate of 288 treatment mixes (adjusted full-factorial trial plan). Log Kp = c + mMF + rR + s + a + b + vV R = Excess molar refraction;  = Dipolarity/Polarizability;  = H-Bond Acidity;  = H-Bond Basicity; V = McGowan atomic volume

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Compounds Penetrants: Substituted phenols (Nonylphenol, Pentachlorophenol, Phenol, - Nitrophenol) Organophosphates (Chlorpyrifos, Ethylparathion, Fenthion, Methylparathion) Triazine Herbicides (Atrazine, Propazine, Simazine, Triazine) Mixture Components: Ethanol, Water, Propylene glycol Methylnicotinate, Sodium lauryl sulfate

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No Mixture Factor Mixture Factor

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Summary of Diffusion Cell Data Improvement of Log Kp Predictability (R 2 ) utilizing Physical Chemical Properties of Mixture Pred versus Obs Residuals No MF 0.58 0 Refractive Index 0.80 0.53 Polarizability 0.76 0.43 log (1/Henry Constant) 0.77 0.45 Analysis demonstrates clear change of Log Kp when MF included. Essential Component investigations grouped MF descriptors into three "descriptor classes," with those above speaking to class individuals with most grounded affiliations.

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Applied MF to two different QSPRs Also led on the accompanying models for instance of general relevance of this approach Potts and Guy (1992) log k p = i + m MF + a log P oct + b MW : Hostynek and Magee (1997) log k p = i + m MF + b MR + c HBA + d HBD Had utilized pointer variable for vehicles

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Hostynek and Magee Potts and Guy

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Isolated Perfused Porcine Skin Flap (IPPSF) Isolated framework with control over physiological parameters and perfusate piece Intact microcirculation with practical epidermis and dermis Large dosing range with unsurprising extrapolation to in vivo Allows for concurrent appraisal of assimilation, skin manner, pharmacokinetics and disturbance Humane option creature demonstrate

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IPPSF Studies fundamentally the same as those depicted for dissemination cells, however investigations are all the more exorbitant and tedious. Utilized Area Under the Curve (AUC) of flux profile as opposed to Kp. Examination An: utilized subset of same compound and blend set as dispersion cell ponders (10 mixes in 50 treatment mixes) (Full Factorial test outline). Examination B: included 11 different mixes and blends for a sum of 21 chemicals in 114 treatment mixes.

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Analysis A (10 chemicals 50 trts)  No Mixture Factor Best Mixture Factor 

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Analysis B (21 chemicals 114 trts)  No Mixture Factor Best Mixture Factor 

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Summary of MF Approach to Date Approach seems vigorous crosswise over various trial models and QSAR approaches Need to pick sub-atomic descriptors that reflect instrument of activity (Abraham display works best of those examined) IPPSF anticipated that would be less anticipated as numerous purposes of connection now present. MF can be a capacity in light of system utilizing blended impact demonstrating strategies. Would descriptors in the QSAR model be distinctive knowing a MF would be utilized? As informational collection grows, concoction induction space will be wealthier and numerous segment MF would be factually identifiable

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Membrane Coated Fiber Array A moment way to deal with anticipate blends Empirical - test construct demonstrate Based in light of GC/MS SPME filaments Validated for forecast of substance assimilation crosswise over porcine skin Holds guarantee to recognize instruments of compound blend associations Overview approach and proof of idea that dermal absorpiton can be anticipated

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Conceptual Basis of MCF to Predict Membrane Interactions Log K p = c + rR + s  + a + b + vV The collaborations reflected in the quality coefficients are what is displayed utilizing the MCF exhibit LFERs can be characterized for K S in skin, and diverse strands PDMS, PA, CarboWax (PEG) LogK S = f(logK MCF1 + logK MCF2 + logK MCF3 ) Not reliant upon writing information

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How It Works A layer is covered on an inactive fiber, MCF. MCFs are submerged into the contributor arrangement, chemicals are divided into the film. MCF is specifically infused into GC/MS for quantitative/subjective investigations. Film Coated Fiber (MCF) Technique

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Permeation Study of a Chemical Mixture with MCF Technique GC/MS Spectra Acquired with the MCF for 30 different natural test mixes

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Experimental Data n o = Maximum penetration sum a = Shape work

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Correlation of Skin Permeability from watery vehicle with segment coefficients of individual MCF PDMS, PA, CarboWax

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Correlation of Skin Permeability with two MCF mixes

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Correlation of Skin Permeability with Three MCF, Partial Regression/Residual Plots

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MCF Array to Predict Skin Kp from Mixtures half Ethanol 1% SLS

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Expand this framework to catch the way of blend collaborations crosswise over solvents utilizing MCF Log K p = c + rR + s  + a + b + vV MCF versus Skin anticipated: a x  Descriptors

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Applicable to any current QSPR display Does not require research center reviews Assumes linearity and freedom of all associations MF could be expressed as an element of properties Laboratory based No compelling reason to know synthetic descriptors Applicable to exceptionally unpredictable

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