Evaluation of interconversion pharmacokinetics of 16α-hydroxycleroda-3,13(14)Z-dien-15,16-olide – a novel HMG-CoA reductase inhibitor and its acid metabolite using multi-compartmental pharmacokinetic model in mice

Abstract

1. 16α-Hydroxycleroda-3,13(14)Z-dien-15,16-olide (4655K-09 or K-09) is a novel clerodane diterpene lactone reported for its anti-hyperlipidemic efficacy. The objective of the present study was to investigate the probable reversible metabolism of 4655K-09 and evaluate its effects on pharmacokinetic (PK) properties.

2. The PK studies were carried out through intravenous (IV) bolus administration of 4655K-09 and K-9T in mice at a dose of 3, 6 and 12 mg/kg separately. The oral PK study of 4655K-09 was carried out at therapeutic dose of 25 mg/kg.

3. The % AUC of metabolite converted to parent upon its administration $\left({\mathrm{\%}\mathrm{ }\mathrm{A}\mathrm{U}\mathrm{C}}_{\mathrm{K}-09}^{\mathrm{K}-9\mathrm{T}}\right)$ was found to be 27.28 ± 2.67. The multi-compartmental interconversion model defined reversible and irreversible clearances along with volumes of distribution for parent and metabolite. The results emphasized that hydrolysis of lactone to acid was more efficient than back conversion to parent due to greater extent of irreversible elimination of acid. Further, the role of interconversion in pharmacokinetics of 4655K-09 was evaluated through secondary parameters like conversion coefficients of parent to metabolite (${\mathrm{K}}_{\mathrm{K}-9\mathrm{T}}^{\mathrm{K}-09}:0.08\pm 0.02$), metabolite to parent (${\mathrm{K}}_{\mathrm{K}-09}^{\mathrm{K}-9\mathrm{T}}$: 0.019 ± 0.001), exposure enhancement (EE: 1.04 ± 0.006), and recycled fraction (RF: 0.042 ± 0.007), highlighted the minimal role of interconversion. The estimation of oral bioavailability remains unaffected when calculated through considering reversible metabolism.

4. The present model-based interconversion pharmacokinetics of 4655K-09 in mice could be further extended to other species to support its development as anti-hyperlipidemic agent.

Keywords:

• 4655K-09
• lactone–acid interconversion
• multi-compartmental interconversion model
• interconversion parameters

Disclosure statement

There is no potential conflict of interest.

Additional information

Funding

We are thankful to Council of Scientific and Industrial Research (CSIR) BSC0102 (THUNDER) project for funding and the Director, CSIR-CDRI, for providing facilities and infrastructure for the study. The authors TSL and SP are thankful to the Council of Scientific & Industrial Research (CSIR) for providing the research fellowship. The CSIR-CDRI communication number of this article is 9665.