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Papers by Beatrice Magnusson

Research paper thumbnail of Bovine-Serum-Albumin-Containing Receptor Phase Better Predicts Transdermal Absorption Parameters for Lipophilic Compounds

The Journal of Investigative Dermatology, Apr 1, 2003

Research paper thumbnail of Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

American Journal of Veterinary Research, Feb 1, 2005

Research paper thumbnail of Enterohepatic circulation: Physiological, pharmacokinetic and clinical implications

Clinical Pharmacokinetics

Research paper thumbnail of Perspectives in Percutaneous Penetration

Research paper thumbnail of Percutaneous Absorption of Steroids: Determination of in vitro Permeability and Tissue Reservoir Characteristics in Human Skin Layers

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 paper thumbnail of The effect of region of application on absorption of ethanol and hexanol through canine skin

Research in Veterinary Science, 2004

Research paper thumbnail of Simple Rules Defining the Potential of Compounds for Transdermal Delivery or Toxicity

Pharmaceutical Research, 2000

Research paper thumbnail of Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin

Journal of Investigative Dermatology, 2004

Research paper thumbnail of Determination of the Effect of Lipophilicity on the in vitro Permeability and Tissue Reservoir Characteristics of Topically Applied Solutes in Human Skin Layers

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Bovine-Serum-Albumin-Containing Receptor Phase Better Predicts Transdermal Absorption Parameters for Lipophilic Compounds

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Enterohepatic Circulation

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.

Research paper thumbnail of Implications for burn shock resuscitation of a new in vivo human vascular microdosing technique (microdialysis) for dermal administration of noradrenaline

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.

Research paper thumbnail of Effect of solute lipophilicity on penetration through canine skin

Australian Veterinary Journal, 2003

Research paper thumbnail of Penetration of a topically applied nonsteroidal anti-inflammatory drug into local tissues and synovial fluid of dogs

American Journal of Veterinary Research, 2005

Research paper thumbnail of Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

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' 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.

Research paper thumbnail of Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

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.

Research paper thumbnail of Veterinary drug delivery: potential for skin penetration enhancement

Advanced Drug Delivery Reviews, 2001

Research paper thumbnail of Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysis

Research paper thumbnail of Bovine-Serum-Albumin-Containing Receptor Phase Better Predicts Transdermal Absorption Parameters for Lipophilic Compounds

The Journal of Investigative Dermatology, Apr 1, 2003

Research paper thumbnail of Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

American Journal of Veterinary Research, Feb 1, 2005

Research paper thumbnail of Enterohepatic circulation: Physiological, pharmacokinetic and clinical implications

Clinical Pharmacokinetics

Research paper thumbnail of Perspectives in Percutaneous Penetration

Research paper thumbnail of Percutaneous Absorption of Steroids: Determination of in vitro Permeability and Tissue Reservoir Characteristics in Human Skin Layers

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 paper thumbnail of The effect of region of application on absorption of ethanol and hexanol through canine skin

Research in Veterinary Science, 2004

Research paper thumbnail of Simple Rules Defining the Potential of Compounds for Transdermal Delivery or Toxicity

Pharmaceutical Research, 2000

Research paper thumbnail of Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin

Journal of Investigative Dermatology, 2004

Research paper thumbnail of Determination of the Effect of Lipophilicity on the in vitro Permeability and Tissue Reservoir Characteristics of Topically Applied Solutes in Human Skin Layers

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Bovine-Serum-Albumin-Containing Receptor Phase Better Predicts Transdermal Absorption Parameters for Lipophilic Compounds

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Enterohepatic Circulation

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.

Research paper thumbnail of Implications for burn shock resuscitation of a new in vivo human vascular microdosing technique (microdialysis) for dermal administration of noradrenaline

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.

Research paper thumbnail of Effect of solute lipophilicity on penetration through canine skin

Australian Veterinary Journal, 2003

Research paper thumbnail of Penetration of a topically applied nonsteroidal anti-inflammatory drug into local tissues and synovial fluid of dogs

American Journal of Veterinary Research, 2005

Research paper thumbnail of Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

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' 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.

Research paper thumbnail of Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

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.

Research paper thumbnail of Veterinary drug delivery: potential for skin penetration enhancement

Advanced Drug Delivery Reviews, 2001

Research paper thumbnail of Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysis