Jim E. Riviere

Safety Evaluation of Sunscreen Formulations Containing Titanium Dioxide and Zinc Oxide Nanoparticles in UVB Sunburned Skin: An In Vitro and In Vivo Study

Sunscreens containing titanium dioxide (TiO(2)) and zinc oxide (ZnO) nanoparticles (NP) are effective barriers against ultraviolet B (UVB) damage to skin, although little is known about their disposition in UVB-damaged skin. Pigs were exposed to UVB that resulted in moderate sunburn. For in vitro studies, skin in flow-through diffusion cells were treated 24 h with four sunscreen formulations as follows: 10% coated TiO(2) in oil/water (o/w), 10% coated TiO(2) in water/oil (w/o), 5% coated ZnO in o/w, and 5% uncoated ZnO in o/w. TiO(2) (rutile, crystallite) primary particle size was 10 × 50 nm with mean agglomerates of 200 nm (range ca. 90 nm--460 nm); mean for ZnO was 140 nm (range ca. 60--200 nm). Skin was processed for light microscopy, scanning (SEM) and transmission electron microscopy (TEM), and time-of-flight secondary ion mass spectrometry (TOF-SIMS). UVB-exposed skin had typical sunburn histology. TEM showed TiO(2) NP 17 layers into stratum corneum (SC), whereas ZnO remained on the surface. TOF-SIMS showed TiO(2) and ZnO epidermal penetration in both treatments. Perfusate analyzed by TEM/energy dispersive x-ray spectroscopy or inductively coupled plasma mass spectrometry detected no Ti or Zn, indicating minimal transdermal absorption. In vivo, skin was dosed at 24 h occluded with formulations and at 48 h. TiO(2) NP in o/w formulation penetrated 13 layers into UVB-damaged SC, whereas only 7 layers in normal skin; TiO(2) in w/o penetrated deeper in UVB-damaged SC. Coated and uncoated Zn NP in o/w were localized to the upper one to two SC layers in all skin. By SEM, NP were localized as agglomerates in formulation on the skin surface and base of hair. TOF-SIMS showed Ti within epidermis and superficial dermis, whereas Zn was limited to SC and upper epidermis in both treatments. In summary, UVB-damaged skin slightly enhanced TiO(2) NP or ZnO NP penetration in sunscreen formulations but no transdermal absorption was detected.

Comparative pharmacokinetics: principles, techniques and applications

Introduction principles of drug movement in the body absorption distribution renal elimination hepatic biotransformation and biliary excretion compartmental models noncompartmental models nonlinear models physiological models dosage regimens simultaneous pharmacokinetics-pharmacodynamics modelling study design and data analysis population pharmacokinetics models and Bayesian forecasting applied to clinical pharmacokinetics dosage adjustment in renal diseases interspecies extrapolations tissue residues and withdrawal times.

Electrically-assisted transdermal drug delivery.

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.

Pharmacokinetics of melamine in pigs following intravenous administration

Melamine-contaminated pet food was recently added as a supplement to livestock feed. There is little or no information concerning the pharmacokinetics of melamine in livestock, and the aim of this study was to obtain pharmacokinetic parameters for this contaminant in pigs. Melamine was administered intravenously to five weanling pigs at a dose of 6.13 mg/kg and plasma samples were collected over 24 h, extracted for melamine, and then analyzed by HPLC-UV. The data was shown to best fit a one-compartment model with melamines half-life of 4.04 (+/- 0.37) h, clearance of 0.11 (+/- 0.01) L/h/kg, and volume of distribution of 0.61 (+/- 0.04) L/kg. These data are comparable to the only mammalian study in rats and suggests that melamine is readily cleared by the kidney and there is unlikely to be significant tissue binding. Further tissue residue studies are required to assess the depletion kinetics of this contaminant in the pig which will determine whether residue levels in the kidney should be of public health concern if pigs were exposed to a similar dose.

Pharmacokinetics of nanomaterials: an overview of carbon nanotubes, fullerenes and quantum dots.

A full understanding of the pharmacokinetic parameters describing nanomaterial disposition in the body would greatly facilitate development of a firm foundation upon which risk assessment could be based. This review focuses on the disposition of carbon based fullerenes and nanotubes, as well as quantum dots (QD) after parenteral administration to primarily rodents. The common theme across all particle types is that a major determinant of nanomaterial disposition is the degree of interaction with the reticuloendothelial (RE) cell system. Small water-soluble particles evading this system may be excreted by the kidney. Larger particles and those with the proper surface charge may get targeted to RE cells in the liver, spleen and other organs. Most nanomaterial kinetics are characterized by relatively short blood half-lives reflecting tissue extraction and not by clearance from the body. In fact, another common attribute to nanomaterial kinetics is retention of particles in the body. Finally, unlike many small organic drugs, nanomaterials may preferentially be trafficked in the body via the lymphatic system that has obvious immunological implications.

Mapping the Surface Adsorption Forces of Nanomaterials in Biological Systems

The biological surface adsorption index (BSAI) is a novel approach to characterize surface adsorption energy of nanomaterials that is the primary force behind nanoparticle aggregation, protein corona formation, and other complex interactions of nanomaterials within biological systems. Five quantitative nanodescriptors were obtained to represent the surface adsorption forces (hydrophobicity, hydrogen bond, polarity/polarizability, and lone-pair electrons) of the nanomaterial interaction with biological components. We have mapped the surface adsorption forces over 16 different nanomaterials. When the five-dimensional information of the nanodescriptors was reduced to two dimensions, the 16 nanomaterials were classified into distinct clusters according their surface adsorption properties. BSAI nanodescriptors are intrinsic properties of nanomaterials useful for quantitative structure-activity relationship (QSAR) model development. This is the first success in quantitative characterization of the surface adsorption forces of nanomaterials in biological conditions, which could open a quantitative avenue in predictive nanomedicine development, risk assessment, and safety evaluation of nanomaterials.

Percutaneous Absorption of Parathion in Vitro in Porcine Skin: Effects of Dose, Temperature, Humidity, and Perfusate Composition on Absorptive Flux

The effect of environmental factors on the percutaneous absorption of parathion in excised porcine skin was assessed in a flow-through diffusion cell system by varying the temperature (T), relative humidity (%RH), perfusate flow rate (F), and composition (porcine serum) at three parathion doses (4, 40, and 400 micrograms/cm2) compared to standard conditions (air temperature = 37 degrees C, perfusate temperature = 37 degrees C, %RH = 60, flow rate = 4 ml/hr, and standard bovine serum albumin medium). Parathion absorption was assessed by monitoring total radiolabeled activity appearing in the perfusate over time. High relative humidity significantly increased parathion penetration, as did two elevated temperature conditions. The effects of flow rate and perfusate composition were variable and dose dependent. In the present studies, lower applied doses appeared to be more sensitive to changes in the environmental conditions studied. These results suggest that these parameters have independent and different degrees of effect on parathion percutaneous absorption. Experimental conditions should be strictly controlled and dose-response studies need to be conducted when evaluating transdermal studies. Finally, if similar effects occur in vivo, the risk assessment calculations on percutaneous absorption should take these parameters into consideration.

The isolated perfused porcine skin flap as an in vitro model for percutaneous absorption and cutaneous toxicology.

The isolated perfused porcine skin flap (IPPSF) is a new perfused skin model which allows in vitro cutaneous pharmacology and toxicology studies to be conducted in a viable skin preparation which has a normal anatomical structure and a functional microcirculation. The purpose of this review is to (1) outline the background of this field which indicated the need for this type of model; (2) outline the surgical procedures needed to create and harvest viable preparations; (3) overview the criteria (biochemical, physiological, and histological) used to assess viability during an experiment; (4) present results of percutaneous absorption, cutaneous metabolism, transdermal delivery (passive and active), and skin distribution experiments conducted to date; (5) present the strategy developed to quantitate percutaneous absorption and cutaneous drug distribution using compartmental and physiological-based pharmacokinetic models; (6) assess the correlation of IPPSF data to in vivo results; (7) define the biochemical, physiological and histological (LM, TEM, enzyme histochemistry) response of the IPPSF to topically applied cutaneous vesicants; (8) overview where this type of in vitro model fits into the overall framework of cutaneous toxicology and pharmacology research; and (9) outline possible paths for future development. This review should provide the reader with an appreciation of some unique problems in this field which require an in vitro model that is closely integrated in structure and function to the in vivo setting.

Identification of the pathway of iontophoretic drug delivery : light and ultrastructural studies using mercuric chloride in pigs

Although electrically assisted transdermal drug delivery has recently achieved a great deal of research attention, the precise anatomical pathway followed by these drugs through the stratum corneum has not been clearly defined. Pigs are an accepted model for studying iontophoretic drug delivery in humans. The purpose of this investigation was to visualize the pathway of ion transport by iontophoresing mercuric chloride. Weanling Yorkshire swine were dosed with 7.4% mercuric chloride in the positive electrode at a current density of 200 µAmp/cm2 applied for 1 hr. Biopsies were immediately taken, exposed to 25% ammonium sulfide vapor to precipitate and localize the mercury, fixed, and processed for light and transmission electron microscopy. The presence of mercury, which appeared as a black precipitate, was confirmed using energy-dispersive X-ray microanalysis. Although some compound penetrated the skin through appendageal pathways, the electron micrographs clearly revealed that mercuric chloride traversed the intact stratum corneum via an intercellular route. Precipitate was also localized in the outer membrane of the mitochondria in the viable epidermal cells, dermal fibroblasts, and capillaries, demonstrating transdermal delivery and systemic exposure to the mercury. These findings have implications for iontophoretic drug delivery, since they allow visualization of the functional “pores” predicted by mathematical models.

Applying the biopharmaceutics classification system to veterinary pharmaceutical products: Part II. Physiological considerations

In comparing product bioavailability across animal species, it is not unusual to observe marked interspecies differences. For many compounds, these differences reflect presystemic drug metabolism. However, a host of other variables must also be considered such as in vivo drug solubility, gastric transit time, intestinal permeability, diet, and species-by-formulation interactions. By combining information on drug solubility and intestinal permeability with an understanding of the interrelationship between pH, product dissolution and gastrointestinal physiology, we attempt to define those conditions under which in vitro dissolution data may be used as a surrogate for data on in vivo bioavailability. We consider the likely physiological causes for species-related differences in the absolute and relative bioavailability of orally administered pharmaceuticals, and examine the potential for these normal interspecies differences to reflect bioavailability changes that can occur with various human pathologies.