Beatrice Magnusson - Academia.edu (original) (raw)

Papers by Beatrice Magnusson

The Journal of Investigative Dermatology, Apr 1, 2003

Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lo... more Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coe⁄cients and membrane retention of a series of aliphatic alcohols (C1ÀC10, log p^0.72 to 4.06) using two di¡erent receptor solutions (water and 4% bovine serum albumin in phosphate-bu¡ered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in sideby-side glass di¡usion cells. Appearance of alcohol in the receptor compartment ¢lled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined.

American Journal of Veterinary Research, Feb 1, 2005

The effects of the vehicles phosphate-buffered saline (PBS), ethanol (EtOH; 50% in PBS w/w) and p... more The effects of the vehicles phosphate-buffered saline (PBS), ethanol (EtOH; 50% in PBS w/w) and propylene glycol (PG; 50% in PBS w/w) and the region of administration on in vitro transdermal penetration of testosterone was investigated in the dog. Skin was harvested from the thorax, neck (dorsal part) and groin regions of greyhounds after euthanasia and stored at À20°C until required. The skin was then de-frosted and placed into Franz-type diffusion cells which were maintained at approximately 32°C by a waterbath. Saturated solutions of testosterone, containing trace amounts of radiolabelled ( 14 C) testosterone, in each vehicle were applied to the outer (stratum corneum) surface of each skin sample and aliquots of receptor fluid were collected at 0, 2, 4, 8, 16, 20, 22 and 24 h and analysed for testosterone by scintillation counting.

Clinical Pharmacokinetics

The aim of this work was to study the skin permeation of ibuprofen, solubilised in o/w nano-emuls... more The aim of this work was to study the skin permeation of ibuprofen, solubilised in o/w nano-emulsions formulated with palm kernel oil esters (PKOE).

Skin Pharmacology and Physiology, 2006

The skin localization of steroids following topical application is largely unknown. We determined... more The skin localization of steroids following topical application is largely unknown. We determined the distribution of five steroids in human skin using excised epidermal, dermal, and full-thickness membranes in vitro. There was no significant difference in steroid maximum flux through epidermal and full-thickness membranes, other than significantly lower fluxes for the most polar steroid, aldosterone. Hydrocortisone had the highest dermal diffusivity and dermal penetration, and the accumulation of hydrocortisone and corticosterone was higher than that of the other steroids. Slower penetration and higher accumulation in the viable epidermis of progesterone in full-thickness skin were consistent with dermal penetration limitation effects associated with high lipophilicity.

Research in Veterinary Science, 2004

The effect of region of application on the percutaneous penetration of solutes with differing lip... more The effect of region of application on the percutaneous penetration of solutes with differing lipophilicity was investigated in canine skin. Skin from the thorax, neck, back, groin, and axilla regions was harvested from Greyhound dogs and placed in Franztype diffusion cells. Radiolabelled ( 14 C) ethanol (Log P 0.19) or hexanol (Log P 1.94) was applied to each skin section for a total of 5 h. The permeability coefficient (k P , cm h À1 ) and residue of alcohol remaining in the skin were significantly (P ¼ 0:001) higher for hexanol compared to ethanol. In contrast, ethanol had a far greater maximum flux (J max , mol (cm 2 ) À1 h À1 ) than hexanol (P ¼ 0:001).

Pharmaceutical Research, 2000

Purpose. Simple rules based on readily accessible physicochemical properties enable identificatio... more Purpose. Simple rules based on readily accessible physicochemical properties enable identification of solutes that penetrate skin very slowly or rapidly. Methods. Literature in vitro maximal flux values (J max ) across human skin were collected for 87 penetrants. Penetrants were assigned as "good" (J max > 10 −5.52 mole·cm −2 ·h −1 ), "bad" (J max < 10 −8.84 mole·cm −2 ·h −1 ) or "intermediate" based on mean ± 1SD. The feasibility of using readily available physicochemical properties, such as molecular weight (MW), melting point (MP,°K), octanol-water partition coefficient (K), water solubility (S, molarity), number of atoms available for H-bonding (HB), in assigning solutes was examined. Results. Good penetrants had MW Յ 152, log S > −2.3, HB Յ 5, log K < 2.6, MP Յ 432. Bad penetrants had MW > 213, log S < −1.6, HB Ն 4, log K > 1.2, MP Ն 223. Discriminant analysis using MW, HB, log K correctly assigned 70% of compounds. Individual success rates were good (88%), intermediate (58%), bad (93%). Aqueous J max data for 148 test solutes were used for validation. Discriminant analysis assigned 76% of compounds, with individual rates of good (76%), intermediate (67%), and bad (97%). No good penetrants were misclassified as bad or vice versa. Conclusions. These rules enable rapid screening of potential drug delivery candidates and environmental exposure risks.

Journal of Investigative Dermatology, 2004

One of the most important determinants of dermatological and systemic penetration after topical a... more One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J max , mol per cm 2 per h) from a given vehicle. In this work, J max values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k p ) are optimally correlated to solute octanol-water partition coefficient (K ow ) and molecular weight (MW) was found to be the dominant determinant of J max for this literature data set: log J max ¼ À3.90-0.0190MW (n ¼ 87, r 2 ¼ 0.847, po0.001). Estimated solubility in octanol (S oc ) was also a determinant, but improvement in the regression by the addition of log S oc was small (r 2 increased to 0.856). Addition of other physicochemical parameters to MW by forward stepwise regression only marginally improved the regression with a melting point (Mpt) term (r 2 ¼ 0.879) and then hydrogen bonding acceptor capability (H a ) (r 2 ¼ 0.917) is significant. Validation of the equation above was carried with a number of other data sets: an aqueous vehicle with full-and split-thickness skin (r 2 ¼ 0.784, n ¼ 56), some pure solutes (r 2 ¼ 0.537, n ¼ 34), an aqueous vehicle with ionizable solutes (r 2 ¼ 0.282, n ¼ 54) and solutes from a propylene glycol vehicle (r 2 ¼ 0.484, n ¼ 36). An analysis of the entire database gave the equation log J max ¼ À4.52-0.0141MW (n ¼ 278, r 2 ¼ 0.688, po0.001), with inclusion of Mpt and H a increasing r 2 to 0.760 (n ¼ 269). Separate analysis of full-and split-thickness skin data confirmed that the dermal resistance term had only a marginal effect on overall J max . Application of the latter model to an in vivo situation where the dermal capillary bed is slightly below the epidermal-dermal junction revealed that the dermal resistance term was unnecessary for in vivo predictions for most solutes.

Journal of Investigative Dermatology, 2003

In order to establish the relationship between solute lipophilicity and skin penetration (includi... more In order to establish the relationship between solute lipophilicity and skin penetration (including £ux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2^C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum £ux and permeability coe⁄cients are compared for each membrane and estimates of alcohol di¡usivity are made based on £ux/concentration data and also the related tissue resistance (the reciprocal of permeability coe⁄cient) for each membrane type. The permeability coe⁄cient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coe⁄cients were related to logP, and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No di¡erence was measured in the di¡usivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower di¡usivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone. Key words: aliphatic alcohols/ permeability coe⁄cient/tissue partitioning/transdermal penetration. J Invest Dermatol 120:759^764, 2003 I t has long been established that the permeability coe⁄cient of topically applied solutes (both drugs and vehicle components) is dependent on their physicochemical characteristics, particularly lipophilicity and molecular size . Changes occur in the physical environment of the skin layers as depth increases from the stratum corneum (SC) through the viable epidermis and into the dermis. These changes may a¡ect the residence time (time required to cross the membrane) and distribution of solutes during the penetration process. reported that materials with good lipid solubility or a high a⁄nity for protein would be concentrated within the skin structure as increasing lipophilicity and protein binding promote reservoir formation.

Journal of Investigative Dermatology, 2003

Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lo... more Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coe⁄cients and membrane retention of a series of aliphatic alcohols (C1ÀC10, log p^0.72 to 4.06) using two di¡erent receptor solutions (water and 4% bovine serum albumin in phosphate-bu¡ered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in sideby-side glass di¡usion cells. Appearance of alcohol in the receptor compartment ¢lled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined.

Clinical Pharmacokinetics, 2002

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, some... more Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Burns, 2012

Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for ... more Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for recruitment of blood during states of hypoperfusion such as during burn shock resuscitation. However, little is known about the blood flow and metabolic consequences seen in the dermis secondary to the use vasoactive drugs (i.e. noradrenaline) for circulatory support. The aims of this study were therefore: to develop an in vivo, human microdosing model based on dermal microdialysis; and in this model to investigate effects on blood flow and metabolism by local application of noradrenaline and nitroglycerin by the microdialysis system simulating drug induced circulatory support. Nine healthy volunteers had microdialysis catheters placed intradermally in the volar surface of the lower arm. The catheters were perfused with noradrenaline 3 or 30 mmol/L and after an equilibrium period all catheters were perfused with nitroglycerine (2.2 mmol/L). Dermal blood flow was measured by the urea clearance technique and by laser Doppler imaging. Simultaneously changes in dermal glucose, lactate, and pyruvate concentrations were recorded. Noradrenaline and nitroglycerine delivered to the dermis by the microdialysis probes induced large time- and dose-dependent changes in all variables. We particularly noted that tissue glucose concentrations responded rapidly to hypoperfusion but remained higher than zero. Furthermore, vasoconstriction remained after the noradrenaline administration implicating vasospasm and an attenuated dermal autoregulatory capacity. The changes in glucose and lactate by vasoconstriction (noradrenaline) remained until vasodilatation was actively induced by nitroglycerine. These findings, i.e., compromised dermal blood flow and metabolism are particularly interesting from the burn shock resuscitation perspective where noradrenaline is commonly used for circulatory support. The importance and clinical value of the results obtained in this in vivo dermal model in healthy volunteers needs to be further explored in burn-injured patients.

Australian Veterinary Journal, 2003

To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series... more To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin

American Journal of Veterinary Research, 2005

American Journal of Veterinary Research, 2004

To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obta... more To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Skin samples from 5 Greyhounds. Skin samples from the dogs&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32 degrees C). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Mean+/-SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01+/-0.05 microg/cm2 of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.

American Journal of Veterinary Research, 2005

To determine the effects of various vehicles on the penetration and retention of hydrocortisone a... more To determine the effects of various vehicles on the penetration and retention of hydrocortisone applied to canine skin. 20 canine skin samples obtained from the thorax, neck, and groin regions of 5 Greyhounds. Skin was harvested from dogs after euthanasia and stored at -20 degrees C until required. The skin was then defrosted and placed into diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of hydrocortisone that contained trace amounts of radiolabelled [14C]-hydrocortisone in each vehicle (ie, PBS solution [PBSS] alone, 50% ethanol [EtOH] in PBSS [wt/wt], and 50% propylene glycol in PBSS [wt/wt]) were applied to the outer (stratum corneum) surface of each skin sample, and aliquots of receptor fluid were collected for 24 hours and analyzed for hydrocortisone. The maximum flux of hydrocortisone was significantly higher for all sites when dissolved in a vehicle containing 50% EtOH, compared with PBSS alone or 50% propylene glycol, with differences more prominent in skin from the neck region. In contrast, higher residues of hydrocortisone were found remaining within the skin when PBSS alone was used as a vehicle, particularly in skin from the thorax and neck. Penetration of topically applied hydrocortisone is enhanced when EtOH is used in vehicle formulation. Significant regional differences (ie, among the thorax, neck, and groin areas) are also found in the transdermal penetration and skin retention of hydrocortisone. Variability in clinical response to hydrocortisone can be expected in relation to formulation design and site of application.

Advanced Drug Delivery Reviews, 2001

A range of topical products are used in veterinary medicine. The efficacy of many of these produc... more A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.

The Journal of Investigative Dermatology, Apr 1, 2003

Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lo... more Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coe⁄cients and membrane retention of a series of aliphatic alcohols (C1ÀC10, log p^0.72 to 4.06) using two di¡erent receptor solutions (water and 4% bovine serum albumin in phosphate-bu¡ered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in sideby-side glass di¡usion cells. Appearance of alcohol in the receptor compartment ¢lled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined.

American Journal of Veterinary Research, Feb 1, 2005

The effects of the vehicles phosphate-buffered saline (PBS), ethanol (EtOH; 50% in PBS w/w) and p... more The effects of the vehicles phosphate-buffered saline (PBS), ethanol (EtOH; 50% in PBS w/w) and propylene glycol (PG; 50% in PBS w/w) and the region of administration on in vitro transdermal penetration of testosterone was investigated in the dog. Skin was harvested from the thorax, neck (dorsal part) and groin regions of greyhounds after euthanasia and stored at À20°C until required. The skin was then de-frosted and placed into Franz-type diffusion cells which were maintained at approximately 32°C by a waterbath. Saturated solutions of testosterone, containing trace amounts of radiolabelled ( 14 C) testosterone, in each vehicle were applied to the outer (stratum corneum) surface of each skin sample and aliquots of receptor fluid were collected at 0, 2, 4, 8, 16, 20, 22 and 24 h and analysed for testosterone by scintillation counting.

Clinical Pharmacokinetics

The aim of this work was to study the skin permeation of ibuprofen, solubilised in o/w nano-emuls... more The aim of this work was to study the skin permeation of ibuprofen, solubilised in o/w nano-emulsions formulated with palm kernel oil esters (PKOE).

Skin Pharmacology and Physiology, 2006

The skin localization of steroids following topical application is largely unknown. We determined... more The skin localization of steroids following topical application is largely unknown. We determined the distribution of five steroids in human skin using excised epidermal, dermal, and full-thickness membranes in vitro. There was no significant difference in steroid maximum flux through epidermal and full-thickness membranes, other than significantly lower fluxes for the most polar steroid, aldosterone. Hydrocortisone had the highest dermal diffusivity and dermal penetration, and the accumulation of hydrocortisone and corticosterone was higher than that of the other steroids. Slower penetration and higher accumulation in the viable epidermis of progesterone in full-thickness skin were consistent with dermal penetration limitation effects associated with high lipophilicity.

Research in Veterinary Science, 2004

The effect of region of application on the percutaneous penetration of solutes with differing lip... more The effect of region of application on the percutaneous penetration of solutes with differing lipophilicity was investigated in canine skin. Skin from the thorax, neck, back, groin, and axilla regions was harvested from Greyhound dogs and placed in Franztype diffusion cells. Radiolabelled ( 14 C) ethanol (Log P 0.19) or hexanol (Log P 1.94) was applied to each skin section for a total of 5 h. The permeability coefficient (k P , cm h À1 ) and residue of alcohol remaining in the skin were significantly (P ¼ 0:001) higher for hexanol compared to ethanol. In contrast, ethanol had a far greater maximum flux (J max , mol (cm 2 ) À1 h À1 ) than hexanol (P ¼ 0:001).

Pharmaceutical Research, 2000

Purpose. Simple rules based on readily accessible physicochemical properties enable identificatio... more Purpose. Simple rules based on readily accessible physicochemical properties enable identification of solutes that penetrate skin very slowly or rapidly. Methods. Literature in vitro maximal flux values (J max ) across human skin were collected for 87 penetrants. Penetrants were assigned as "good" (J max > 10 −5.52 mole·cm −2 ·h −1 ), "bad" (J max < 10 −8.84 mole·cm −2 ·h −1 ) or "intermediate" based on mean ± 1SD. The feasibility of using readily available physicochemical properties, such as molecular weight (MW), melting point (MP,°K), octanol-water partition coefficient (K), water solubility (S, molarity), number of atoms available for H-bonding (HB), in assigning solutes was examined. Results. Good penetrants had MW Յ 152, log S > −2.3, HB Յ 5, log K < 2.6, MP Յ 432. Bad penetrants had MW > 213, log S < −1.6, HB Ն 4, log K > 1.2, MP Ն 223. Discriminant analysis using MW, HB, log K correctly assigned 70% of compounds. Individual success rates were good (88%), intermediate (58%), bad (93%). Aqueous J max data for 148 test solutes were used for validation. Discriminant analysis assigned 76% of compounds, with individual rates of good (76%), intermediate (67%), and bad (97%). No good penetrants were misclassified as bad or vice versa. Conclusions. These rules enable rapid screening of potential drug delivery candidates and environmental exposure risks.

Journal of Investigative Dermatology, 2004

One of the most important determinants of dermatological and systemic penetration after topical a... more One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J max , mol per cm 2 per h) from a given vehicle. In this work, J max values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k p ) are optimally correlated to solute octanol-water partition coefficient (K ow ) and molecular weight (MW) was found to be the dominant determinant of J max for this literature data set: log J max ¼ À3.90-0.0190MW (n ¼ 87, r 2 ¼ 0.847, po0.001). Estimated solubility in octanol (S oc ) was also a determinant, but improvement in the regression by the addition of log S oc was small (r 2 increased to 0.856). Addition of other physicochemical parameters to MW by forward stepwise regression only marginally improved the regression with a melting point (Mpt) term (r 2 ¼ 0.879) and then hydrogen bonding acceptor capability (H a ) (r 2 ¼ 0.917) is significant. Validation of the equation above was carried with a number of other data sets: an aqueous vehicle with full-and split-thickness skin (r 2 ¼ 0.784, n ¼ 56), some pure solutes (r 2 ¼ 0.537, n ¼ 34), an aqueous vehicle with ionizable solutes (r 2 ¼ 0.282, n ¼ 54) and solutes from a propylene glycol vehicle (r 2 ¼ 0.484, n ¼ 36). An analysis of the entire database gave the equation log J max ¼ À4.52-0.0141MW (n ¼ 278, r 2 ¼ 0.688, po0.001), with inclusion of Mpt and H a increasing r 2 to 0.760 (n ¼ 269). Separate analysis of full-and split-thickness skin data confirmed that the dermal resistance term had only a marginal effect on overall J max . Application of the latter model to an in vivo situation where the dermal capillary bed is slightly below the epidermal-dermal junction revealed that the dermal resistance term was unnecessary for in vivo predictions for most solutes.

Journal of Investigative Dermatology, 2003

In order to establish the relationship between solute lipophilicity and skin penetration (includi... more In order to establish the relationship between solute lipophilicity and skin penetration (including £ux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2^C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum £ux and permeability coe⁄cients are compared for each membrane and estimates of alcohol di¡usivity are made based on £ux/concentration data and also the related tissue resistance (the reciprocal of permeability coe⁄cient) for each membrane type. The permeability coe⁄cient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coe⁄cients were related to logP, and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No di¡erence was measured in the di¡usivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower di¡usivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone. Key words: aliphatic alcohols/ permeability coe⁄cient/tissue partitioning/transdermal penetration. J Invest Dermatol 120:759^764, 2003 I t has long been established that the permeability coe⁄cient of topically applied solutes (both drugs and vehicle components) is dependent on their physicochemical characteristics, particularly lipophilicity and molecular size . Changes occur in the physical environment of the skin layers as depth increases from the stratum corneum (SC) through the viable epidermis and into the dermis. These changes may a¡ect the residence time (time required to cross the membrane) and distribution of solutes during the penetration process. reported that materials with good lipid solubility or a high a⁄nity for protein would be concentrated within the skin structure as increasing lipophilicity and protein binding promote reservoir formation.

Journal of Investigative Dermatology, 2003

Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lo... more Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coe⁄cients and membrane retention of a series of aliphatic alcohols (C1ÀC10, log p^0.72 to 4.06) using two di¡erent receptor solutions (water and 4% bovine serum albumin in phosphate-bu¡ered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in sideby-side glass di¡usion cells. Appearance of alcohol in the receptor compartment ¢lled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined.

Clinical Pharmacokinetics, 2002

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, some... more Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Burns, 2012

Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for ... more Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for recruitment of blood during states of hypoperfusion such as during burn shock resuscitation. However, little is known about the blood flow and metabolic consequences seen in the dermis secondary to the use vasoactive drugs (i.e. noradrenaline) for circulatory support. The aims of this study were therefore: to develop an in vivo, human microdosing model based on dermal microdialysis; and in this model to investigate effects on blood flow and metabolism by local application of noradrenaline and nitroglycerin by the microdialysis system simulating drug induced circulatory support. Nine healthy volunteers had microdialysis catheters placed intradermally in the volar surface of the lower arm. The catheters were perfused with noradrenaline 3 or 30 mmol/L and after an equilibrium period all catheters were perfused with nitroglycerine (2.2 mmol/L). Dermal blood flow was measured by the urea clearance technique and by laser Doppler imaging. Simultaneously changes in dermal glucose, lactate, and pyruvate concentrations were recorded. Noradrenaline and nitroglycerine delivered to the dermis by the microdialysis probes induced large time- and dose-dependent changes in all variables. We particularly noted that tissue glucose concentrations responded rapidly to hypoperfusion but remained higher than zero. Furthermore, vasoconstriction remained after the noradrenaline administration implicating vasospasm and an attenuated dermal autoregulatory capacity. The changes in glucose and lactate by vasoconstriction (noradrenaline) remained until vasodilatation was actively induced by nitroglycerine. These findings, i.e., compromised dermal blood flow and metabolism are particularly interesting from the burn shock resuscitation perspective where noradrenaline is commonly used for circulatory support. The importance and clinical value of the results obtained in this in vivo dermal model in healthy volunteers needs to be further explored in burn-injured patients.

Australian Veterinary Journal, 2003

To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series... more To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin

American Journal of Veterinary Research, 2005

American Journal of Veterinary Research, 2004

To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obta... more To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Skin samples from 5 Greyhounds. Skin samples from the dogs&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32 degrees C). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Mean+/-SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01+/-0.05 microg/cm2 of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.

American Journal of Veterinary Research, 2005

To determine the effects of various vehicles on the penetration and retention of hydrocortisone a... more To determine the effects of various vehicles on the penetration and retention of hydrocortisone applied to canine skin. 20 canine skin samples obtained from the thorax, neck, and groin regions of 5 Greyhounds. Skin was harvested from dogs after euthanasia and stored at -20 degrees C until required. The skin was then defrosted and placed into diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of hydrocortisone that contained trace amounts of radiolabelled [14C]-hydrocortisone in each vehicle (ie, PBS solution [PBSS] alone, 50% ethanol [EtOH] in PBSS [wt/wt], and 50% propylene glycol in PBSS [wt/wt]) were applied to the outer (stratum corneum) surface of each skin sample, and aliquots of receptor fluid were collected for 24 hours and analyzed for hydrocortisone. The maximum flux of hydrocortisone was significantly higher for all sites when dissolved in a vehicle containing 50% EtOH, compared with PBSS alone or 50% propylene glycol, with differences more prominent in skin from the neck region. In contrast, higher residues of hydrocortisone were found remaining within the skin when PBSS alone was used as a vehicle, particularly in skin from the thorax and neck. Penetration of topically applied hydrocortisone is enhanced when EtOH is used in vehicle formulation. Significant regional differences (ie, among the thorax, neck, and groin areas) are also found in the transdermal penetration and skin retention of hydrocortisone. Variability in clinical response to hydrocortisone can be expected in relation to formulation design and site of application.

Advanced Drug Delivery Reviews, 2001

A range of topical products are used in veterinary medicine. The efficacy of many of these produc... more A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.