Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Preclinical Pharmacokinetic Evaluation of β-Lapachone: Characteristics of Oral Bioavailability and First-Pass Metabolism in Rats

  • Kim, Iksoo (College of Pharmacy, Chung-Ang University) ;
  • Kim, Hyeongmin (College of Pharmacy, Chung-Ang University) ;
  • Ro, Jieun (College of Pharmacy, Chung-Ang University) ;
  • Jo, Kanghee (College of Pharmacy, Chung-Ang University) ;
  • Karki, Sandeep (College of Pharmacy, Chung-Ang University) ;
  • Khadka, Prakash (College of Pharmacy, Chung-Ang University) ;
  • Yun, Gyiae (Department of Food Science and Technology, Chung-Ang University) ;
  • Lee, Jaehwi (College of Pharmacy, Chung-Ang University)
  • Received : 2015.03.17
  • Accepted : 2015.03.31
  • Published : 2015.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

${\beta}$-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of ${\beta}$-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of ${\beta}$-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of ${\beta}$-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of ${\beta}$-lapachone was 15.5%. The considerable degradation of ${\beta}$-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of ${\beta}$-lapachone may be resulted from the first-pass metabolic degradation of ${\beta}$-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.

Keywords

References

  1. Blanco, E., Bey, E. A., Khemtong, C., Yang, S. G., Setti-Guthi, J., Chen, H., Kessinger, C. W., Carnevale, K. A., Bornmann, W. G., Boothman, D. A. and Gao, J. (2010) Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res. 70, 3896-3904. https://doi.org/10.1158/0008-5472.CAN-09-3995
  2. Byun, S. J., Son, Y., Cho, B. H., Chung, H.-T. and Pae, H.-O. (2013) ${\beta}$-Lapachone, a substrate of NAD(P)H:quinone oxidoreductase, induces anti-inflammatory heme oxygenase-1 via AMP-activated protein kinase activation in RAW264.7 macrophages. J. Clin. Biochem. Nutr. 52, 106-111. https://doi.org/10.3164/jcbn.12-80
  3. Crooke, R. M., Graham, M. J., Martin, M. J., Lemonidis, K. M., Wyrzykiewiecz, T. and Cummins, L. L. (2000) Metabolism of antisense oligonucleotides in rat liver homogenates. J. Pharmacol. Exp. Ther. 292, 140-149.
  4. Dong, Y., Chin, S. F., Blanco, E., Bey, E. A., Kabbani, W., Xie, X. J., Bornmann, W. G., Boothman, D. A. and Gao, J. (2009) Intratumoral delivery of beta-lapachone via polymer implants for prostate cancer therapy. Clin. Cancer Res. 15, 131-139. https://doi.org/10.1158/1078-0432.CCR-08-1691
  5. Hao, H., Wang, G., Cui, N., Li, J., Xie, L. and Ding, Z. (2007) Identification of a novel intestinal first pass metabolic pathway: NQO1 mediated quinone reduction and subsequent glucuronidation. Curr. Drug Metab. 8, 137-149. https://doi.org/10.2174/138920007779816011
  6. Koo, T. S., Kim, D. H., Ahn, S. H., Kim, K. P., Kim, I. W., Seo, S. Y., Suh, Y. G., Kim, D. D., Shim, C. K. and Chung, S. J. (2005) Comparison of pharmacokinetics of loxoprofen and its active metabolites after an intravenous, intramuscular, and oral administration of loxoprofen in rats: evidence for extrahepatic metabolism. J. Pharm. Sci. 94, 2187-2197. https://doi.org/10.1002/jps.20451
  7. Lee, J. H., Cheong, J., Park, Y. M. and Choi, Y. H. (2005) Down-regulation of cyclooxygenase-2 and telomerase activity by ${\beta}$-lapachone in human prostate carcinoma cells. Pharmacol. Res. 51, 553-560 https://doi.org/10.1016/j.phrs.2005.02.004
  8. Miao, X. S., Song, P., Savage, R. E., Zhong, C., Yang, R.-Y., Kizer, D., Wu, H., Volckova, E., Ashwell, M. A., Supko, J. G., He, X. and Chan, T. C. (2008) Identification of the in vitro metabolites of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; ${\beta}$-lapachone) in whole blood. Drug Metab. Dispos. 36, 641-648. https://doi.org/10.1124/dmd.107.018572
  9. Nasongkla, N., Wiedmann, A. F., Bruening, A., Beman, M., Ray, D., Bornmann, W. G., Boothman, D. A. and Gao J. (2003) Enhancement of solubility and bioavailability of ${\beta}$-lapachone using cyclodextrin inclusion complexes. Pharm. Res. 20, 1626-1633. https://doi.org/10.1023/A:1026143519395
  10. Park, M.-T., Song, M.-J., Lee, H., Oh, E.-T., Choi, B.-H., Jeong, S.-Y., Choi, E.-K. and Park, H.J. (2011) ${\beta}$-lapachone significantly increases the effect of ionizing radiation to cause mitochondrial apoptosis via JNK activation in cancer cells. PLoS One 6, e25976. https://doi.org/10.1371/journal.pone.0025976
  11. Savage, R. E., Tyler, A. N., Miao, X.-S. and Chan, T. C. K. (2008) Identification of a novel glucosylsulfate conjugate as a metabolite of 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, ${\beta}$-lapachone) in mammals. Drug Metab. Dispos. 36, 753-758. https://doi.org/10.1124/dmd.107.018655
  12. Subramanian, N., Subhabrata, R., Ghosal, S. K., Bhadra, R. and Moulik, S. P. (2004) Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib. Biol. Pharm. Bull. 27, 1993-1999. https://doi.org/10.1248/bpb.27.1993
  13. Takano, R., Furumoto, K., Shiraki, K., Takata, N., Hayashi, Y., Aso, Y. and Yamashita, S. (2008) Rate-limiting steps of oral absorption for poorly water-soluble drugs in dogs; prediction from a miniscale dissolution test and a physiologically-based computer simulation. Pharm. Res. 25, 2334-2344. https://doi.org/10.1007/s11095-008-9637-9
  14. Tzeng, H. P., Ho, F. M., Chao, K. F., Kuo, M. L., Lin-Shiau, S. Y. and Liu, S. H. (2003) ${\beta}$-Lapachone reduces endotoxin-induced macrophage activation and lung edema and mortality. Am. J. Respir. Crit. Care Med. 168, 85-91. https://doi.org/10.1164/rccm.200209-1051OC

Cited by

  1. Lapachol and lapachone analogs: a journey of two decades of patent research(1997-2016) vol.27, pp.10, 2017, https://doi.org/10.1080/13543776.2017.1339792
  2. Enhancing Oral Absorption of β-Lapachone: Progress Till Date vol.42, pp.1, 2017, https://doi.org/10.1007/s13318-016-0369-7
  3. Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures vol.41, pp.6, 2016, https://doi.org/10.1007/s13318-015-0310-5
  4. Activation of NQO-1 mediates the augmented contractions of isolated arteries due to biased activity of soluble guanylyl cyclase in their smooth muscle vol.391, pp.11, 2018, https://doi.org/10.1007/s00210-018-1548-7
  5. Mechanically Robust Gastroretentive Drug-Delivery Systems Capable of Controlling Dissolution Behaviors of Coground β-Lapachone vol.11, pp.6, 2015, https://doi.org/10.3390/pharmaceutics11060271
  6. Anticancer Potential of Resveratrol, β-Lapachone and Their Analogues vol.25, pp.4, 2015, https://doi.org/10.3390/molecules25040893
  7. In silico, in vitro and in vivo evaluation of natural Bignoniaceous naphthoquinones in comparison with atovaquone targeting the selection of potential antimalarial candidates vol.401, pp.None, 2020, https://doi.org/10.1016/j.taap.2020.115074
  8. The possibility of low isomerization of β-lapachone in the human body vol.29, pp.3, 2015, https://doi.org/10.12793/tcp.2021.29.e16
  9. Nanocomposite gels of poloxamine and Laponite for β-Lapachone release in anticancer therapy vol.163, pp.None, 2015, https://doi.org/10.1016/j.ejps.2021.105861