In vitrometabolism of KBH-A40, a novelδ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

Abstract

1. The metabolism of KBH-A40, a novel -lactam-based histone deacetylase (HDAC) inhibitor, was investigated in vitro using human liver microsomes and serum. After 60-min incubation in human liver microsomes with -nicotinamide adenine dinucleotide phosphate (NADPH) or uridine diphosphate glucuronic acid (UDPGA), the residual KBH-A40 was 90.6% AE 5.1% and 28.9% AE 2.0% (t 1/2 ¼ 26 min), respectively, suggesting that KBH-A40 is likely predominantly metabolized by glucuronidation, rather than by cytochrome P450 (CYP)-mediated oxidation. Consistently, KBH-A40 glucuronide was the only metabolite identified following incubations of KBH-A40 with human liver microsomes in the presence of both NADPH and UDPGA.2. KBH-A40 was not notably degraded when incubated with human serum for 60 min. In contrast, KBH-A40 was rapidly hydrolysed to its carboxylic acid form in rat serum (t 1/2 ¼ 13 min).3. Taken collectively, the results suggest that KBH-A40 is likely metabolized in man predominantly by glucuronidation of its hydroxamic acid moiety, with negligible biotransformation elsewhere in the molecule.

Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats

“…Taken together, these findings suggest that the rapid hydrolysis in the plasma, exerting an extensive first-pass effect, could be a major reason for the poor oral absorption of KBH-A40. It has been reported by the present authors that KBH-A40 was degraded rapidly in the presence of UDPGA by human liver microsomes and its glucuronide conjugate was identified by using liquid chromatography hybrid quadrupole time-of-flight mass spectrometry analysis (Kim et al, 2008). In this study, our results showed that KBH-A40 was degraded rapidly in the presence of UDPGA by rat liver microsomes.…”

“…Despite this property, the oral bioavailability of KBH-A40 was found to be low (14.2%-14.8%). In our previous study (Kim et al, 2008), KBH-A40 was shown to be rapidly metabolized by hydrolysis to its carboxylate in rat serum. Consistent with this in vitro result, the current pharmacokinetics study demonstrates that KBH-A40 is hydrolyzed rapidly in vivo to its carboxylate after i.v.…”

“…We have also reported the results of our recent in vitro investigation to characterize their drug metabolism properties using the lead compound, KBH-A40, as a model compound (Kim et al, 2008). In the previous report (Kim et al, 2008), KBH-A40 was shown to be readily metabolized to its glucuronide conjugate by human liver microsomes; Although KBH-A40 was not degraded notably in human serum, it was shown to be rapidly hydrolyzed to its carboxylic acid form in rat serum.…”

“…Our previous study showed that KBH-A40 was metabolized rapidly by glucuronidation in liver microsomes (Kim et al, 2008). In this study, a qualitative LC-MS/MS analysis was carried out to identify KBH-A40 glucuronide in the rat plasma samples obtained following the pharmacokinetics experiments described above.…”

Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method

“…Metabolic stability is considered an important property of NCEs and is usually quantified by monitoring the disappearance of the parent compound over time in an in vitro system to determine the metabolic half-life (t 1/2 ) and intrinsic clearance (CL int ) [3,4]. Results obtained from in vitro metabolic stability experiments are used to estimate and predict clearance (CL) in vivo at the early stages of drug discovery.…”