Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site.

OBJECTIVE: To describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration. STUDY DESIGN: Randomized crossover experiment; prospective study. ANIMALS: Eleven healthy adult horses between 6 and 20 years of age and weighing 487-592 kg. METHODS: In the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg(-1)) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg(-1) SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility. RESULTS: Following IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg(-1) minute(-1) and volume of distribution at steady-state was 3.16 ± 0.65 L kg(-1). Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported. CONCLUSIONS AND CLINICAL RELEVANCE: Buprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.

Elimination kinetics of tilmicosin following intramammary administration in lactating dairy cattle.

OBJECTIVE: To determine elimination kinetics of tilmicosin in milk following intramammary administration in lactating dairy cattle. DESIGN: Prospective pharmacokinetic study. ANIMALS: 6 lactating dairy cows. PROCEDURES: Following collection of baseline milk samples, 1,200 mg (4 mL) of tilmicosin was infused into the left front and right rear mammary glands of each cow. Approximately 12 hours later, an additional 1,200 mg of tilmicosin was infused into the left front and right rear glands after milking. Milk samples were then collected from each gland at milking time for 40 days. Concentration of tilmicosin was determined by means of ultraperformance liquid chromatography-mass spectrometry, and a milk withdrawal interval for tilmicosin was calculated on the basis of the tolerance limit method. RESULTS: Although there was considerable variation between glands, concentration of tilmicosin was high in milk from treated glands and had a long half-life in treated and untreated glands. Tilmicosin was detected in all treated glands for the entire 40-day study period and was detected in untreated glands for approximately 30 to 35 days. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that tilmicosin should not be administered by the intramammary route in lactating dairy cows. Milk from all glands of any cows accidentally treated should be discarded for a minimum of 82 days following intramammary administration.

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 melamine's 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.

Vehicle effects on in vitro transdermal absorption of sevoflurane in the bullfrog, Rana catesbeiana.

The experimental objectives were to identify a vehicle which produces a homogenous formulation when combined with the anesthetic solution sevoflurane and understand the dermal absorption of sevoflurane in silastic membranes and amphibian skin in vitro utilizing a flow-through diffusion system. Seven vehicles were evaluated in varying ratios with 5 formulations resulting in the desired homogenous consistency for practical application. Sevoflurane diffusion across silastic membranes was influenced by pluronic/lecithin organogel (PLO), pluronic F 127 20% gel, and sterile lube. Flux and permeability across silastic membranes were significantly greater in sterile lube than in the other formulations. While no significant vehicle effects were observed in bullfrog skin, the flux-time profiles suggest that sevoflurane diffusion in bullfrog skin may be positively influenced by PLO. Future in vivo studies are required to assess sevoflurane retention after removal of these formulations to more accurately control the plane of anesthesia in amphibians.

Partitioning behavior of aromatic components in jet fuel into diverse membrane-coated fibers.

Jet fuel components are known to partition into skin and produce occupational irritant contact dermatitis (OICD) and potentially adverse systemic effects. The purpose of this study was to determine how jet fuel components partition (1) from solvent mixtures into diverse membrane-coated fibers (MCFs) and (2) from biological media into MCFs to predict tissue distribution. Three diverse MCFs, polydimethylsiloxane (PDMS, lipophilic), polyacrylate (PA, polarizable), and carbowax (CAR, polar), were selected to simulate the physicochemical properties of skin in vivo. Following an appropriate equilibrium time between the MCF and dosing solutions, the MCF was injected directly into a gas chromatograph/mass spectrometer (GC-MS) to quantify the amount that partitioned into the membrane. Three vehicles (water, 50% ethanol-water, and albumin-containing media solution) were studied for selected jet fuel components. The more hydrophobic the component, the greater was the partitioning into the membranes across all MCF types, especially from water. The presence of ethanol as a surrogate solvent resulted in significantly reduced partitioning into the MCFs with discernible differences across the three fibers based on their chemistries. The presence of a plasma substitute (media) also reduced partitioning into the MCF, with the CAR MCF system being better correlated to the predicted partitioning of aromatic components into skin. This study demonstrated that a single or multiple set of MCF fibers may be used as a surrogate for octanol/water systems and skin to assess partitioning behavior of nine aromatic components frequently formulated with jet fuels. These diverse inert fibers were able to assess solute partitioning from a blood substitute such as media into a membrane possessing physicochemical properties similar to human skin. This information may be incorporated into physiologically based pharmacokinetic (PBPK) models to provide a more accurate assessment of tissue dosimetry of related toxicants.

Dermatotoxicity of cutting fluid mixtures:in vitro and in vivo studies.

Cutting fluids are widely used in the metal-machining industry to lubricate and reduce heat generation when metals are cut by a metal-cutting tool. These cutting fluids have caused occupational irritant contact dermatitis (OICD), and many of the additives used in these cutting fluid mixtures are thought to be responsible for OICD in workers. The purpose of this study was to assess single or various combinations of these additives in initiating the OICD response following an acute 8-hour exposure in porcine skin in vivo and in vitro using the isolated perfused porcine skin flap (IPPSF) and human epidermal keratinocytes (HEK). Pigs (n = 4) were exposed to 5% mineral oil (MO) or 5% polyethylene glycol (PEG) aqueous mixtures containing various combinations of 2% triazine (TRI), 5% triethanolamine (TEA), 5% linear alkylbenzene sulfonate (LAS), or 5% sulfurized ricinoleic acid (SRA). Erythema and edema were evaluated and skin biopsies for histopathology were obtained at 4 and 8 hours. IPPSFs (n = 4) were exposed to control MO or PEG mixtures and complete MO or PEG mixtures, and perfusate samples were collected hourly to determine interleukin- (IL-) 8 release. The only significant (p < 0.05) mixture effects observed in IPPSFs were with SRA + MO that caused an increase in IL-8 release after 1 or 2 hours' exposure. In vivo exposure to TRI alone appeared to increase erythema, edema, and dermal inflammation compared to the other additives, while SRA alone was least likely to initiate a dermal inflammatory response. In 2-component mixture exposures, the presence of TRI appeared to increase the dermal inflammatory response at 4 and 8 hours especially with the PEG mixtures. In the 3- and 4-component mixtures, MO mixtures are more likely to incite an inflammatory response than PEG mixtures. TRI exhibited the highest toxicity toward HEK, which correlates well to the in vivo irritation and morphology results. In summary, these preliminary studies suggest that the biocide, TRI, is the more potent of the 4 performance additives in causing dermal irritation, and this may vary depending on whether the worker is exposed to a synthetic (PEG)- or MO-based fluid. These findings will however require further clinical studies to validate these acute dermal effects as well as human cumulative irritation following exposure to similar cutting fluid formulations in the workplace.

NDELA and nickel modulation of triazine disposition in skin.

Cutting fluids can become contaminated with metals (e.g., nickel, Ni) and nitrosamines (e.g., N-nitrosodiethanolamine, NDELA) and there is concern that these classes of contaminants can modulate dermal disposition and ultimately the toxicity of cutting fluid additives, such as irritant biocides (e.g., triazine). Biocides are added to these formulations to prevent bacterial degradation of commercial cutting fluids. The purpose of this study was to assess the dermal absorption and skin deposition of 14C-triazine when topically applied to porcine skin in an in vitro flow-through diffusion cell system as aqueous soluble oil (mineral oil, MO) or aqueous synthetic (polyethylene glycol, PEG) mixtures. 14C-Triazine mixtures were formulated with NDELA and/or Ni, or with a combination of three additional cutting fluid additives; namely, 5% linear alkylbenzene sulfonate (LAS), 5% triethanolamine (TEA) and 5% sulfurized ricinoleic acid. Neither Ni nor NDELA was absorbed during these 8-h studies. However, 14C-triazine absorption ranged from 2.72 to 3.29% dose in MO and 2.29-2.88% dose in PEG with significantly greater triazine absorption in MO than PEG when all additives and contaminates were present. The difference between these two diluents was most pronounced when NDELA and/or Ni were present in cutting fluids. These contaminants also enhanced triazine deposition on the skin surface and skin tissues especially with PEG-based mixtures. In essence, the dermal disposition of irritant biocides could be dependent on whether the worker is exposed to a soluble oil or synthetic fluid when these contaminants are present. Workers should therefore not only be concerned about dermatotoxicity of these contaminants, but also the modulated dermal disposition of cutting fluid additives when these contaminants are present in cutting fluid formulations.

Physicochemical determinants of linear alkylbenzene sulfonate (LAS) disposition in skin exposed to aqueous cutting fluid mixtures.

Linear alkylbenzene sulfonate (LAS) is added to cutting fluid formulations to enhance the performance of metal machining operations, but this surfactant can cause contact dermatitis in workers involved in these operations. The purpose of this study was to determine how cutting fluid additives influence dermal disposition of 14C-LAS in mineral oil- or polyethylene glycol 200 (PEG)-based mixtures when topically applied to silastic membranes and porcine skin in an in vitro flow-through diffusion cell system. 14C-LAS mixtures were formulated with three commonly used cutting fluid additives; 0 or 2% triazine (TRI), 0 or 5% triethanolamine (TEA), and 0 or 5% sulfurized ricinoleic acid (SRA). LAS absorption was limited to less than a 0.5% dose and the additives in various combinations influenced the physicochemical characteristics of the dosing mixture. LAS was more likely to partition into the stratum corneum (SC) in mineral oil mixtures, and LAS absorption was significantly greater in the complete mixture. TRI enhanced LAS transport, and the presence of SRA decreased LAS critical micelle concentration (CMC) which reduced LAS monomers available for transport. TEA increased mixture viscosity, and this may have negated the apparent enhancing properties of TRI in several mixtures. In summary, physicochemical interactions in these mixtures influenced availability of LAS for absorption and distribution in skin, and could ultimately influence toxicological responses in skin.