Transport of hop aroma compounds across Caco-2 monolayers.

Although being reported and used as a sedative remedy for several years, the bioactive principle of hop preparations is still not decisively clarified. Understanding absorption and transformation processes of potential physiologically active constituents is essential to evaluate the likeliness of biological effects on humans. Therefore, single hop aroma compounds as well as digestive transformation products thereof have been investigated in view of their human intestinal absorption, applying Caco-2 transport experiments as well as investigations on potential biotransformation processes. Selective and sensitive identification and quantification were thereby achieved by application of two-dimensional high resolution gas chromatography-mass spectrometry in conjunction with stable isotope dilution analysis, leading to the determination of apparent permeability values by different mathematical approaches considering sink and non-sink conditions. Overall, calculated permeability values ranged from 2.6 × 10(-6) to 1.8 × 10(-4) cm s(-1) with all mathematical approaches, indicating high absorption potential and almost complete bioavailability for all tested compounds with hydroxyl-functionalities. Considering this high permeability together with the high lipophilicity of these substances, a passive transcellular uptake route can be speculated. Investigated sesquiterpenes and ß-myrcene showed flat absorption profiles while the investigated esters showed decreasing profiles. In view of the lipophilic and volatile nature of the investigated substances, special attention was paid to recovery and mass balance determination. Furthermore, in the course of the transport experiments of 1-octen-3-ol and 3-methyl-2-buten-1-ol, additional biotransformation products were observed, namely 3-octanone and 3-methyl-2-butenal, respectively. The absence of these additional substances in control experiments strongly indicates an intestinal first-pass metabolism of the α,ß-unsaturated alcohols 1-octen-3-ol and 3-methyl-2-buten-1-ol in Caco-2 cells.

Safety assessment of 1,2-glycols as used in cosmetics.

Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.

Fragrance material review on 6-ethyl-3-methyloct-6-en-1-ol.

A toxicologic and dermatologic review of 6-ethyl-3-methyloct-6-en-1-ol when used as a fragrance ingredient is presented.

Fragrance material review on 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative.

A toxicologic and dermatologic review of 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative when used as a fragrance ingredient is presented.

Fragrance material review on dihydromyrcenol.

A toxicologic and dermatologic review of dihydromyrcenol when used as a fragrance ingredient is presented.

Effect of transport inhibitors and additional anti-HIV drugs on the movement of lamivudine (3TC) across the guinea pig brain barriers.

To treat human immunodeficiency virus (HIV) within the central nervous system (CNS), levels of anti-HIV drugs in the brain must reach therapeutic concentrations. The ability of (-)-2'-deoxy-3'-thiacytidine (3TC; lamivudine) to cross the blood-brain and blood-cerebrospinal fluid (CSF) barriers, alone and in combination with additional nucleoside analogs, was investigated. The bilateral in situ guinea pig brain perfusion method, linked to high-performance liquid chromatography analyses, was used to examine 3TC uptake into brain and CSF simultaneously. The influence of transport inhibitors and additional nucleoside analogs on this uptake was investigated. 3TC movement across the blood-CSF barrier was examined in more detail by the isolated choroid plexus model. 3TC movement across the brain barriers and subsequent accumulation in the brain and CSF was low. However, 3TC uptake from blood into choroid plexus (a potential CNS target for HIV treatment) was significant, and was facilitated by a digoxin-sensitive transporter. Another transporter was identified, which removed 3TC from the choroid plexus. Abacavir, 2'3'-didehydro-3'deoxythymidine, and 3'-azido 3'-deoxythymidine did not interact with 3TC at either of the brain barriers to affect CNS concentrations of 3TC. However, a significant interaction between 3TC and 2'3'-dideoxyinosine was observed at the choroid plexus, and it may prove beneficial to select drug combinations where no such interaction is indicated.

Effect of solute lipophilicity on penetration through canine skin.

OBJECTIVE: To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin. DESIGN: Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radiolabelled (14C) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19-3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (kP, cm/h), maximum flux (Jmax, mol/cm2/h) and residue remaining within the skin were determined. RESULTS: The kP increased with increasing lipophilicity (6.2 x 10(-4) +/- 1.6 x 10(-4) cm/h for ethanol to 1.8 x 10(-2) +/- 3.6 x 10(-3) cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. CONCLUSION: Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin.

Effect of excipients on the stability and aerosol performance of nebulized aviscumine.

Pulmonary delivery is an attractive alternative route to deliver protein drugs that are currently delivered by injection. Inhalation therapy via nebulizers is a well accepted way for pulmonary application of proteins considering the formulation difficulties of MDIs or DPIs. This research presents the effect of variable excipients on the stability and aerosol performance of freeze-dried aviscumine after reconstitution and nebulization. Aviscumine formulations containing 100 mmol/L Tris buffer, 0.1% (w/v) Polysorbate 80, 0.01% (w/v) Na(2)-EDTA and 8% (w/v) Hydroxyethyl starch have been lyophilized and reconstituted with a buffered isotonic solution pH 8. The aviscumine activity was determined by a binding assay directly after reconstitution and after nebulization with a PariBoy air-jet nebulizer, a Multisonic and a Systam ultrasonic nebulizer. The stabilization of aviscumine by the addition of variable buffer salts to the reconstitution medium, such as 50, 100, and 200 mmol/L Tris buffer, 20 and 100 mmol/L phosphate buffer, and 20 and 100 mmol/L Tricine buffer, was studied. About 50% of aviscumine activity was lost after 20 min nebulization time without any additives. Nevertheless, higher buffer concentrations confer greater stability. About 70% of the aviscumine activity could be retained by the addition 0.03% octanoyl-N-methylglucamide and 100 mmol/L Tricine to the reconstitution medium.

The effect of the nature of H-bonding groups on diffusion through PDMS membranes saturated with octanol and toluene.

The permeation of a series of structurally related compounds across silicone membranes (PDMS) was studied. The PDMS was saturated either with toluene, to mimic a functionally inert barrier, or octanol, to mimic the polar/hydrogen bonding environment of the stratum corneum lipid barrier. Phenol, salicylic acid, benzoic acid, anisole, phenylethanol and benzyl alcohol were chosen in an attempt to relate permeation to their different H-bonding capabilities. The flux was lower through the octanol system suggesting retardation by polar/H-bonding interactions. Separation of the permeability coefficient into its thermodynamic (partition coefficient) and kinetic (diffusion coefficient) terms suggests that the effect of altering polarity within the membrane has a greater impact on the diffusion of permeant rather than its chemical potential within the membrane.

Designing multidrug-resistance modulators circumventing the reverse pH gradient in tumours.

Multidrug-resistant tumours often exhibit a reverse pH gradient (acid outside), as they have an acid extracellular pH (pHe) and a neutral alkaline intracellular pH (pHi). This study was designed to test the hypothesis that the ability of lipophilic drugs to mediate multidrug resistance (MDR) reversal by interacting with the membrane phospholipids may be correlated with pH in resistant tumours. The permeation properties of five MDR modulators were therefore studied at 37 degrees C by quantifying their ability to induce the leakage of Sulfan blue through unilamellar anionic liposomes, over the range pH 6.5-7.7, and in the absence of any membrane potential (pHe = pHi). The dye leakage induced by two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was found to significantly increase with the pH of the medium (P < 0.001), whereas that induced by a non-ionic detergent (Triton X-100) showed almost no pH-dependent variations. This process was a cooperative one (0.8 < Hill coefficient < 8.5) and the permeation doses inducing 50% dye leakage (PD50) ranged from 1.6 to 36.0 mM. The permeation ability of the MDR modulators (log(1/PD50)) significantly increased with their octanol-buffer distributions (logD) (slope = 0.35+/-0.06; y intercept = 1.65 +/- 0.14; P < 0.0001) and significantly decreased with their net electric charge (z) (slope = -0.48+/-0.07; y intercept = 2.85+/-0.08; P < 0.0001). A highly significant multiple correlation was found to exist between the variations of log(1/PD50) with those of logD and z (dlog(1/PD50)/dlogD = 0.21 +/- 0.05; dlog(1/PD50)/dz = -0.34+/-0.07; y intercept = 2.27+/-0.17; P < 0.000001). The results provide evidence that in resistant tumours (acid pHe and neutral alkaline pHi), the MDR reversal might be enhanced by favourable drug-membrane interactions if the modulators are designed in the form of highly lipophilic (logP approximately equals 4) mono-basic drugs with a near neutral pKa (pKa approximately equals 7-8).

Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption.

PURPOSE: Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development. METHODS: Liposome distribution coefficients measured titrimetrically and solubility data at pH 6.8 were used to characterize 21 structurally diverse ionizable drugs covering a range from <5% to almost complete absorption. RESULTS: A sigmoidal relationship was found between the percentage of human passive intestinal absorption and a new absorption potential parameter calculated from liposome distribution data and the solubility-dose ratio. In contrast, the human absorption data did not correlate with an octanol-based absorption potential or partitioning data alone. Poor correlations were found between liposome and octanol partitioning of ionic species or nonionic bases indicating the profound differences of the partitioning systems. CONCLUSIONS: Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans. Profound differences between liposome and octanol partitioning were found for a highly diverse set of species. This titration technique may serve to generate liposome partitioning data for the selection and optimization of lead compounds and in drug development.

Effect of nanoparticles on transdermal drug delivery.

The purpose of the present study was to assess by in vitro means the effect of poly (methylmethacrylate) nanoparticles and poly (butylcyanoacrylate) nanoparticles on transdermal drug delivery. Methanol and octanol were chosen as test permeants. In order to distinguish between thermodynamic effect and those due to biological consequences, two different membranes were employed, i.e., full thickness hairless mouse skin and silicone elastomer sheeting (175 microns). It is evident that poly (methylmethacrylate) nanoparticles and poly (butylcyanoacrylate) nanoparticles increase the permeability of methanol through hairless mouse skin by a factor of 1.2-2. The permeability of lipophilic octanol is either unaffected by nanoparticles or decreases as a function of nanoparticle concentration depending on the lipophilicity of the polymer material.

Esterification of chiral secondary alcohols with fatty acid in organic solvents by polyethylene glycol-modified lipase.

Lipase from Pseudomonas fragi 22.39B was modified with polyethylene glycol. The modified lipase (PEG-lipase) was soluble and active in organic solvents such as benzene and 1,1,1-trichloroethane. PEG-lipase catalyzed esterification of chiral secondary alcohols with fatty acids in benzene and exhibited preference for R isomers over S isomers. Km and Vmax values for each isomer of various alcohols were obtained by kinetic study of the esterification in benzene. PEG-lipase-catalyzed esterification leads to optical resolution of a racemic alcohol.