Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity

Abstract

Raltegravir (RAL), an HIV-1 integrase inhibitor, has been administered as part of antiretroviral therapy (ART). Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, co-administration of proton pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [βCD], random methyl-βCD [RAM-βCD], and hydroxypropyl-βCD [HP-βCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with βCD, RAM-βCD, and HP-βCD attenuated this effect in cell-based assays. These findings suggest that βCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as βCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.

Antifungal potency of terbinafine as a therapeutic agent against Exophiala dermatitidis in vitro

“…A nicotinamide adenine dinucleotide (NAD) was docked to the SQLE ED in the same manner as the crystal structure of SQLE Hum using SeeSAR v13.1 (BioSolveIT GmbH, Sankt Augustin, Germany). 48 Next, we determined the binding pocket of TRB using the 6C6N and clinically isolated TRB-resistant amino acid mutations of T. rubrum and performed the docking simulation of TRB to the SQLE ED . Molecular graphics and analyses were performed using UCSF Chimera (https://www.rbvi.ucsf.edu/chimera).…”