Preclinical pharmacokinetic investigation of the bioavailability and skin distribution of HY-072808 Ointment, a novel drug candidate for the treatment of atopic dermatitis, in minipigs by a newly LC-MS/MS method

Xenobiotica. 2024 Mar 19:1-18. doi: 10.1080/00498254.2024.2333007. Online ahead of print.ABSTRACT1. HY-072808 is a novel phosphodiesterase 4 inhibitor clinically used for topical atopic dermatitis treatment. Cytochrome P450 enzymes are involved in transforming it into major metabolite ZZ-24. An efficient UPLC-MS/MS method was established to detect HY-072808 and ZZ-24 in plasma and skin tissues of minipigs.2. One-step protein precipitation was performed with acetonitrile. Subsequently, elution was served with a methanol and water gradient containing 0.1% formic acid for 3.5 min. The plasma and skin tissue concentrations of HY-072808 and ZZ-24 showed good linearity from 0.200-200 ng/mL.3. The experimental minipigs exhibited low systemic exposure and bioavailability of 3.1%-7.6% after transdermal application of 1%-4% HY-072808 ointment. Multiple topical administrations over seven consecutive days showed a minor accumulation in systemic exposure, with accumulation factors of 2.3 and 4.0 for HY-072808 and ZZ-24, respectively.4. The distribution of HY-072808 ointment among different cortical layers in minipigs was studied for the first time. Following transdermal application of 2% HY-072808 ointment, the concentration in plasma and skin tissues in the order of epidermis > dermis > subcutaneous tissue ≈ subcutaneous muscle ≈ plasma; at 48 hours after the administration, the epidermis and dermis still had a high concentration of the drug.PMID:38501457 | DOI:10.1080/00498254...
Source: Xenobiotica - Category: Research Authors: Source Type: research