Exploring the biotransformation of N‐(2‐hydroxyphenyl)‐2‐propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies.

Mendieta‐Wejebe, Jessica Elena; Silva‐Trujillo, Arianna; Bello, Martiniano; Mendoza‐Figueroa, Humberto L.; Galindo‐Alvarez, Norma Lizeth; Albores, Arnulfo; Tamay‐Cach, Feliciano; Rosales‐Hernández, Martha Cecilia; Romero‐Castro, Aurelio; Correa‐Basurto, José

Objectives: N‐(2‐hydroxyphenyl)‐2‐propylpentanamide (HO‐AAVPA), a derivative of valproic acid (VPA), has been proposed as a potential anticancer agent due to its improved antiproliferative effects in some cancer cell lines. Although there is evidence that VPA is metabolized by cytochrome P450 2C11 rat isoform, HO‐AAVPA CYP‐mediated metabolism has not yet been fully explored. Therefore, in this work, the biotransformation of HO‐AAVPA by CYP2C11 was investigated. Methods: Kinetic parameters and spectral interaction between HO‐AAVPA and CYP were evaluated using rat liver microsomes. The participation of CYP2C11 in metabolism of HO‐AAVPA was confirmed by cimetidine (CIM) inhibition assay. Docking and molecular dynamics simulations coupled to MMGBSA methods were used in theoretical study. Key findings: HO‐AAVPA is metabolized by CYP enzymes (KM = 38.94 µm), yielding a hydroxylated metabolite according to its HPLC retention time (5.4 min) and MS analysis (252.2 m/z). In addition, CIM inhibition in rat liver microsomes (Ki = 59.23 µm) confirmed that CYP2C11 is mainly involved in HO‐AAVPA metabolism. Furthermore, HO‐AAVPA interacts with CYP2C11 as a type I ligand. HO‐AAVPA is stabilized at the CYP2C11 ligand recognition site through a map of interactions similar to other typical CYP2C11 substrates. Conclusion: Therefore, rat liver CYP2C11 isoform is able to metabolize HO‐AAVPA.

VALPROIC acid; ACID derivatives; FORECASTING; IN vitro studies; CYTOCHROME P-450; BENZENESULFONAMIDES

Journal of Pharmacy & Pharmacology, 2020, Vol 72, Issue 7, p938

0022-3573

Academic Journal

10.1111/jphp.13270