PKQuest: volatile solutes - application to enflurane,nitrous oxide,halothane, methoxyflurane and toluene pharmacokinetics

BACKGROUND: The application of physiologically based pharmacokinetic models (PBPK) to human studies has been limited by the lack of the detailed organ information that is required for this analysis. PKQuest is a new generic PBPK that is designed to avoid this problem by using a set of "standard human" default parameters that are applicable to most solutes. RESULTS: PKQuest is used to model the human pharmacokinetics of the volatile solutes. A "standard human" value for the lipid content of the blood and each organ (klip) was chosen. This set of klip and the oil/water partition coefficient then specifies the organ/blood partition for each organ. Using this approach, the pharmacokinetics of inert volatile solute is completely specified by just 2 parameters: the water/air and oil/water partition coefficients. The model predictions of PKQuest were in good agreement with the experimental data for the inert solutes enflurane and nitrous oxide and the metabolized solutes halothane and toluene. METHODS: The experimental data that was modeled was taken from previous publications. CONCLUSIONS: This approach greatly increases the predictive power of the PBPK. For inert volatile solutes the pharmacokinetics are determined just from the water/air and oil/water partition coefficient. Methoxyflurane cannot be modeled by this PBPK because the arterial and end tidal partial pressures are not equal (as assumed in the PBPK). This inequality results from the "washin-washout" artifact in the large airways that is established for solutes with large water/air partition coefficients.PKQuest and the worked examples are available on the web www.pkquest.com.     

Surface behaviour of bile salts and tetrahydrolipstatin at air/water and oil/water interfaces.

The surface behaviour of two bile salts, sodium deoxycholate (NaDC) and sodium taurodeoxycholate (NaTDC), as well as that of tetrahydrolipstatin (THL), a potent gastrointestinal lipase inhibitor, was studied at air/water and oil/water interfaces, using interfacial tensiometry methods. The surface behaviour of NaDC and NaTDC was comparable at both oil/water and air/water interfaces. A fairly compact interfacial monolayer of bile salts is formed well below the critical micellar concentration (CMC) and can help to explain the well-known effects of bile salts on the kinetic behaviour of pancreatic lipases. Using the Wilhelmy plate technique, the surface pressure-molecular area curves recorded with THL at the air/water interface showed a collapse point at a surface pressure of 24.5 mN.m(-1), corresponding to a molecular area of 70 A(2). Surprisingly, using the oil drop method, a limiting molecular area of 160 A(2) was found to exist at the oil/water interface. On the basis of the above data, space-filling models were proposed for bile salts and THL at air/water and oil/water interfaces.     

DETERMINATION OF SENSORY OIL-WATER PARTITION COEFFICIENTS OF SINGLE AROMA COMPOUNDS COMBINING PANELIST FREE INTENSITY RATING AND THEORETICAL MODELING OF ODOR INTENSITY

Using an intensity rating with no external calibration, experiments were designed to measure the sensory oil-water partition coefficients of four aroma molecules (benzaldehyde, ethyl butyrate, linalool and acetophenone) as the ratios of concentration producing stimuli of equivalent intensities. Flavored water and oil phases were successively assessed for odor intensity by 24 panelists who were given total freedom regarding scaling strategy. Each session combined five concentration levels of three out of the four studied aromas in a solvent (water or oil). A predominant concentration effect was found for each aroma in both solvents and concentration dependencies of perceived intensity above water and oil were similar. Experimental data were modeled with Fechner, Stevens and Hill equations. Combining results above water and oil solutions to feed a common model led to the evaluation of an overall sensory oil-water partition coefficient for each aroma compound. All three models produced similar partition coefficient values for each aroma that were lower than the related instrumental partition coefficients. Biases previously detected when external calibration had been used were reduced in a large proportion while suggested enhancement of odor intensity by water vapor could not be excluded.     

Influence of Temperature and Oil Content on the Soil/Air Partition Coefficient for Hexachlorobenzene in Oil-Contaminated Rice Paddy Field Soil

The soil/air partition coefficients (K _SA ) for hexachlorobenzene (HCB) in oil-contaminated (crude oil and diesel) rice paddy field soils were measured in a solid fugacity meter at different oil concentrations over the temperature range of 5 to 30°C at 100% relative humidity. The results showed that values of K _SA increased with a decrease of temperature. As for oil content, there is a critical separate phase concentration (CSPC) above which K _SA increased with increasing of oil content. When oil content is above CSPC, oil plays a role as a separate phase that enhances the sorption capacity of the soil. At a given temperature (20°C) values of CSPC depended on the natural organic matter (NOM) contents of the soil, while for a given oil concentration they depended on the temperature. The normalized oil/air partition coefficients ) for HCB deduced from K _SA for oils and experimentally determined with crude oil/quartz sand system were similar and 0.7–7 times higher than the normalized organic/air partition coefficient ), which implied that oil was a super sorbent. The enthalpies (ΔH_SA) for crude oil and diesel were 64.9 and 55.7 kJ mol^?1, respectively.     

Identification of air phase retronasal and orthonasal odorant pairs

Identifications (IDs) of paired retronasal and orthonasal odorants were studied, with stimuli limited to air phase. Odorants were liquid extracts of plant materials, sold as food flavorings, matched by each subject both for retronasal-only and orthonasal-only air phase intensities and then learned to 100% correct veridical name retronasal-only and orthonasal-only IDs. Subjects were tested for ID of (a) retronasal-only and orthonasal-only odorants, (b) homogeneously paired odorant (the same odorant in retronasal and orthonasal locations), and (c) heterogeneously paired odorants (different odorants in retronasal and orthonasal locations). Paired odorants were presented in two different sequences: retronasal location odorant smelled first or orthonasal location odorant smelled first. IDs were reported after odorants were removed. Results were as follows: (a) no significant differences between correct ID of odorants when in retronasal-only versus orthonasal-only locations, although percent correct IDs were lower for half the retronasal-only location odorants; (b) correct ID of a homogeneously paired odorant equaled or exceeded its unpaired ID, with two successive, identical IDs reported on the majority of its trials; (c) with heterogeneous pairs, for all odorants when in the orthonasal location of a pair, correct ID occurred less often than when these odorants were presented orthonasal-only, but for odorants in the retronasal location, correct ID equaled or exceeded retronasal-only correct ID; and (d) perceived order of presentation of heterogeneous pairs was the reverse of the physically presented sequence for both retronasal-first and orthonasal-first conditions. The heterogeneous odorant ID outcome supports the concept that processing of retronasal and orthonasal odorants differ, and the perceived reversal of the presented sequence is in agreement with the importance of recency in odorant memory.     

Fostering in sheep. III. Facilitation by the use of odorants

Lambs were thoroughly anointed with various odoriferous substances to test the facilitatory effects on substitutive fostering on to multiparous Merino ewes held in individual pens. The ewes were first familiarised with an odorant by anointing their own lamb with it 24 h before a similarly anointed foster lamb was presented. The odorants were neatsfoot oil, wool wax, vegetable oil, butyric and propionic acids, mercaptoethanol, vanillin, methyl salicylate and eucalyptus oil. Acceptance of foster lambs was assessed over the next 48 h. Odorants were not applied to the ewes.All eight foster lambs treated with neatsfoot oil were accepted within 24 h; seven immediately. There were few immediate acceptances with the other odorants, but from two to five lambs out of groups of six were permanently fostered by 48 h. Only one foster lamb was accepted in the control group of 12 in which no odorant was used. Fostering was most successful with neatsfoot oil and wool wax, both substances that originated from ruminant skin.Fostering was less successful in tests that omitted pre-exposure of the ewes to their own lambs treated with neatsfoot oil, wool wax or vegetable oil.Toxicity problems were encountered with ethanol solutions of mercaptoethanol, methyl salicylate, eucalyptus oil and neatsfoot oil.     

Application of Ultra-Centrifugation and Bench-Top <Superscript>19</Superscript>F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field ¹⁹F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and ¹⁹F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.     

Odorant detection capability of QCR sensors coated with plasma deposited organic films.

Odorant-detection experiments were conducted on major single-odor substances in various types of botanical species. The sensing devices we used were quartz-crystal resonators (QCRs), radio-frequency (RF) sputtered with amino acids or polymers. The odorants were generated at very low concentrations (ppb level) by using the diffusion-tube method. The tested odorants were detected at concentrations between 0.3 and 940 ppb. These deposited films had high partition coefficients for the odorants, confirming their high sensitivity to organic vapors, especially to terpenoids. This indicates that the odorant solvation is due to odorant-film interaction related to Gibbs free energy.     

Oxygen transfer in three-phase airlift and stirred tank reactors using silicone oil as transfer vector

The use of organic liquids as vectors to enhance mass transfer has been applied since the 1970s. However, mass transfer in three-phase reactors is only partially understood. This paper aimed to characterize oxygen transfer in three-phase reactors containing air as gas, silicone oil as vector and water as aqueous phase. A mass transfer model that considers separately air/vector, vector/water and air/water oxygen transfers was developed. The model was used to describe oxygen transfer in airlift and stirred tank reactors containing from 0 to 50% of silicone oil. Under the experimental conditions, silicone oil had a positive effect on the overall oxygen transfer. In both reactor designs, the maximum overall oxygen transfer was observed with 10% silicone oil which was increased by 65 and 84% in the airlift and stirred reactor, respectively, compared to reactors operated without silicone oil. The overall transfer increase was mainly due to an enhanced air/water transfer. With 10% silicone oil, the air/water contribution to the overall oxygen transfer was 94.7 and 93.0% for the airlift and stirred reactor, respectively.     

Experimental and numerical determination of odorant solubility in nasal and olfactory mucosa

Odorant deposition in the nasal and olfactory mucosas is dependent on a number of factors including local air/odorant flow distribution patterns, odorant mucosal solubility and odorant diffusive transport in the mucosa. Although many of these factors are difficult to measure, mucosal solubility in the bullfrog mucus has been experimentally determined for a few odorants. In the present study an experimental procedure was combined with computational fluid dynamic (CFD) techniques to further describe some of the factors that govern odorant mucosal deposition. The fraction of odorant absorbed by the nasal mucosa (eta) was experimentally determined for a number of odorants by measuring the concentration drop between odorant 'blown' into one nostril and that exiting the contralateral nostril while the subject performed a velopharyngeal closure. Odorant concentrations were measured with a photoionization detector. Odorants were delivered to the nostrils at flow rates of 3.33 and 10 l/min. The velopharyngeal closure nasal air/odorant flows were then simulated using CFD techniques in a 3-D anatomically accurate human nose modeland the mucosal odorant uptake was numerically calculated. The comparison between the numerical simulations and the experimental results lead to an estimation of the human mucosal odorant solubility and the mucosal effective diffusive transport resistance. The results of the study suggest that the increase in diffusive resistance of the mucosal layer over that of a thin layer of water seemed to be general and non-odorant-specific; however, the mucosa solubility was odorant specific and usually followed the trend that odorants with lower water solubility were more soluble in the mucosa than would be predicted from water solubility alone. The ability of this approach to model odorant movement in the nasal cavity was evaluated by comparison of the model output with known values of odorant mucosa solubility.     

Optimization and monitoring of water soluble substrate for synthesis of mannosylerythritol lipids by Pseudozyma antarctica (ATCC 32657)

Biosurfactants are amphipathic molecules, consisting of hydrophobic and hydrophilic domains, which can partition at the interfaces between different fluid phases, such as oil/water or water/air interfaces. Mannosylerithritol lipids (MELs) are a type of glycolipid. The yeast Candida (Pseudozyma) antarctica (ATCC 32657) secretes an extracellular MEL, with biosurfactant properties, when grown on a water soluble and insoluble substrate, such as glycerine or oils. Value added MEL was biologically synthesized, by using two different types of honey as natural and newer water soluble carbon source. Those types of honey as a carbon source were optimized at different concentration of total carbohydrate present in the honey. Further optimized substrate concentration of honey was monitored for 15 days, for studies of MEL yield and cell growth concentration per day on shake flask batch culture. Surfactant properties, such as surface tension, interfacial tension, foaming, emulsification and wetting of MEL, were observed. Produced MEL was confirmed by thin layer chromatography (TLC), Fourier Transform Infrared (FTIR) spectra, and ¹H Nuclear Magnetic Resonance (NMR) techniques.     

Oil/water and pre-emulsified oil/water (PIT) dispersions in a stirred vessel: Implications for fermentations

This study examines dispersions of rapeseed oil (RSO) in water by mechanical agitation under conditions mimicking those found in certain antibiotic fermentations; for example, in the presence of air, antifoam, and finely divided CaCO(3) particles. A problem with residual oil has been reported for such fermentations, and it has been suggested that the use of pre-emulsified oil can reduce this problem. Hence, the dispersion of a pre-emulsified oil produced by the "phase inversion temperature (PIT) method" has been evaluated. In both cases, the volume fraction of oil was 2%. For the RSO systems, a relatively high agitation speed was required to disperse the oil, especially in the presence of the particles and, when the agitation was stopped, separation occurred rapidly. The Sauter mean drop diameters depended on the system, being at an average energy dissipation rate of approximately 0.9 W kg(-1), 180 microm for RSO/water, 130 microm for RSO/water(antifoam)/air, 580 microm for RSO/water/CaCO(3), and 850 microm for RSO/water(antifoam)/air/CaCO(3). For the same four systems, the PIT emulsion, once dispersed, was very stable and the drop size was essentially independent of the operating conditions, with a Sauter mean diameter of approximately 0.3 microm. The implications of these findings for fermentations in which oil is used as a carbon source are assessed.     

Characterization of Foam- and Emulsion-stabilizing Functions of Enzymatically Modified Proteins with Surfactancy

A papain-catalyzed reaction involving covalent incorporation of l-leucine n-alkyl ester is available for producing an enzymatically modified protein (EMP) with surfactancy [Agric. Biol. Chem., 45, 1621 (1981)]. In the present work we used gelatin as a starting material and incorporated l-leucine n-hexyl ester to produce a whippable EMP and l-leucine n-dodecyl ester to produce an emulsifiable EMP. A foam system formed with the whippable EMP was much stabler than that formed with sodium dodecylsulfate. The emulsifiable EMP also gave a much stabler oil-in-water emulsion than Tween-80 did. The stability of the emulsion formed with EMP was not affected by the presence of NaCl at a very high concentration. The observed foam and emulsion stabilities were well explained by the data for decreased mobility of the involved water protons. These results may indicate that EMP molecules, when arranged at the air/water or oil/water interface, can bind a part of the water to form thick barriers which prevent the air or oil particles from coalescing.     

Effects of two neem insecticide formulations on the attractiveness, acceptability and suitability of diamondback moth larvae to the parasitoid, Diadegma mollipla (Holmgren) (Hym., Ichneumonidae)

Abstract:  Behavioural responses of female Diadegma mollipla to volatiles from cabbage plants and host-infested [ Plutella xylostella (L.)] cabbage plants sprayed with two neem insecticide formulations were investigated in a Y-tube olfactometer. Parasitoids were significantly more attracted to volatiles from cabbage and host-infested cabbage sprayed with the powder formulation than to clean air. In contrast, parasitoid response to volatiles from cabbage and host-infested cabbage sprayed with the oil formulation was not significantly different from clean air. In choice tests between infested plants sprayed with water (control) or the powder formulation, parasitoids showed no preference for volatiles from either of the treatments. In similar tests with the oil formulation, parasitoids showed a preference for volatiles from control plants over plants sprayed with the oil formulation. In host acceptance and suitability tests, parasitism rates in the neem- and water-sprayed hosts were, with one exception, not significantly different. However, the neem-sprayed larvae died earlier than control larvae and were therefore not able to support parasitoid development. The implication of these findings for the combined use of neem insecticides and parasitoids in the management of P. xylostella is discussed.     

Honeybees Learn Odour Mixtures via a Selection of Key Odorants

Background

The honeybee has to detect, process and learn numerous complex odours from her natural environment on a daily basis. Most of these odours are floral scents, which are mixtures of dozens of different odorants. To date, it is still unclear how the bee brain unravels the complex information contained in scent mixtures.

Methodology/Principal Findings

This study investigates learning of complex odour mixtures in honeybees using a simple olfactory conditioning procedure, the Proboscis-Extension-Reflex (PER) paradigm. Restrained honeybees were trained to three scent mixtures composed of 14 floral odorants each, and then tested with the individual odorants of each mixture. Bees did not respond to all odorants of a mixture equally: They responded well to a selection of key odorants, which were unique for each of the three scent mixtures. Bees showed less or very little response to the other odorants of the mixtures. The bees'' response to mixtures composed of only the key odorants was as good as to the original mixtures of 14 odorants. A mixture composed of the other, non-key-odorants elicited a significantly lower response. Neither an odorant''s volatility or molecular structure, nor learning efficiencies for individual odorants affected whether an odorant became a key odorant for a particular mixture. Odorant concentration had a positive effect, with odorants at high concentration likely to become key odorants.

Conclusions/Significance

Our study suggests that the brain processes complex scent mixtures by predominantly learning information from selected key odorants. Our observations on key odorant learning lend significant support to previous work on olfactory learning and mixture processing in honeybees.     

Membrane bioreactor with a porous hydrophobic membrane as a gas-liquid contactor for waste gas treatment

A novel type of bioreactor for waste gas treatment has been designed. The reactor contains a microporous hydrophobic membrane to create a large interface between the waste gas and the aqueous phase. To test the new reactor, propene was chosen because of its high air/water partition coefficient, which causes a low water concentration and hampers its removal from air. Propene transfer from air to a suspension of propene-utilizing Xanthobacter Py2 cells in the membrane bioreactor proved to be controlled by mass transfer in the liquid phase. The resistance of the membrane was negligible. Simulated propene transfer rates agreed well with the experimental data. A stable biofilm of Xanthobacter Py2 developed on the membrane during prolonged operation. The propene flux into the biofilm was 1 x 10(-6) mol m(-2) s(-1) at a propene concentration of 9.3 x 10(-2) mol m(-3) in the gas phase. (c) 1995 John Wiley & Sons, Inc.     

A simple and flexible device to odorize large stimulation areas

This paper describes a flow dilution olfactometer which allowsthe odorization of large stimulation areas and the easy manipulationof several odorants and/or concentrations. Generation of theodorized air is performed by mixing in two steps the odor vaporcontained in Tedlar bags with a pure air stream flowing continuouslyout of a nozzle. Discrete concentration values are obtainedby using pre-adjusted needle valves to change the vapor flowsampled in the bags. This kind of olfactometer was utilizedto study odor coding in the olfactory bulbs of rats and rabbits.Five Odorants were delivered at concentrations ranging from2 x 10^-4 to 1.5 x 10^-2 of the saturated vapor pressure. Measurementsshowed that lower concentrations can be obtained by fillingthe bags with a more diluted odor vapor. Furthermore, the numberof test odorants can be increased at low cost by increasingthe number of Tedlar bags.     

Cross-cultural comparison of data using the odor stick identification test for Japanese (OSIT-J)

A new olfactory test, the odor stick identification test for Japanese (OSIT-J), has been developed in Japan. To determine if the OSIT-J would be effective cross-culturally, we administered the test to 52 US and 50 Japanese subjects reporting normal olfactory function. The average composite OSIT-J test score for US subjects was significantly lower (77%) than that for Japanese subjects (94%, P < 0.0001). Both US and Japanese subjects correctly identified eight of the 13 odorants included in the OSIT-J with scores of 80% or higher. However, for five odorants, the US subjects' scores fell below 80% and were consistently lower than Japanese subjects, presumably reflecting cultural differences in odor experience. Most of the US subjects found the OSIT-J to be easy, interesting, pleasant, and short in duration. Although the 13-odorant OSIT-J was found to be suitable for testing US populations, elimination of five test odorants that were unfamiliar to US subjects significantly enhanced the test's effectiveness. Findings from this study emphasize the importance of identifying test odorants that may have a cultural bias, a crucial issue when comparing data obtained from different smell tests used at smell and taste centers around the world.