Development of an In-vitro Drug Delivery Efficiency Test for a Pulmonary Toxicokinetic Pig Study

Abstract

Background: Since their appearance on the drugs of abuse market, synthetic cannabinoids (SCs) are gaining increasing toxicological relevance. They are consumed without knowledge of their toxicokinetic (TK) and toxicodynamic properties and human studies are not allowed due to ethical reasons. A controlled animal TK study following nebulization of 4-ethylnaphthalene-1-yl-(1-pentylindole- 3-yl)methanone (JWH-210), 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) as well as Δ9-tetrahydrocannabinol (THC) to pigs should be helpful for better interpretation of analytical results in cases of misuse or poisoning. As a prerequisite, an in-vitro test system mimicking a ventilated pig had to be developed to determine the quantity and reproducibility of which drug dose is delivered to the pig lung.

Methods: JWH-210, RCS-4, and THC (1 mg in 2 mL ethanol each) were nebulized during ventilation using an ultrasonic nebulizer. The drug aerosol was delivered via the inspiratory limb and the endotracheal tube passing through a glass fiber filter (n = 6). The drugs were extracted from the filters using ethanol and ultrasonication. After several dilution steps and adding an internal standard solution, the extracts were analyzed by LC-MS/MS.

Results: Extraction of the nebulized drugs revealed delivery efficiencies of 78.8 ± 5.0% for JWH-210, 70.5 ± 6.9% for RCS-4, and 70.8 ± 7.9% for THC. The loss of about 20-30% of the administered dose might be attributable to retention in the nebulizer device or adhesion of the aerosol particles to the tube wall.

Conclusion: Nevertheless, regarding delivery efficiencies, the minor standard deviations indicate an acceptable reproducibility, suggesting that this administration system is suitable for application in TK studies.