Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 14;24(2):283.
doi: 10.3390/molecules24020283.

Pharmacokinetics, Tissue Distribution, Plasma Protein Binding Studies of 10-Dehydroxyl-12-Demethoxy-Conophylline, a Novel Anti-Tumor Candidate, in Rats

Chengjun Jiang  1 , Jie Li  2   3 , Xianghai Cai  4 , Nini Li  5 , Yan Guo  6 , Dianlei Wang  7
Affiliations

Pharmacokinetics, Tissue Distribution, Plasma Protein Binding Studies of 10-Dehydroxyl-12-Demethoxy-Conophylline, a Novel Anti-Tumor Candidate, in Rats

Chengjun Jiang et al. Molecules. .

Abstract

10-Dehydroxyl-12-demethoxy-conophylline is a natural anticancer candidate. The motivation of this study was to explore the pharmacokinetic profiles, tissue distribution, and plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline in Sprague Dawley rats. A rapid, sensitive, and specific ultra-performance liquid chromatography (UPLC) system with a fluorescence (FLR) detection method was developed for the determination of 10-dehydroxyl-12-demethoxy-conophylline in different rat biological samples. After intravenous (i.v.) dosing of 10-dehydroxyl-12-demethoxy-conophylline at different levels (4, 8, and 12 mg/kg), the half-life t1/2α of intravenous administration was about 7 min and the t1/2β was about 68 min. The AUC0→∞ increased in a dose-proportional manner from 68.478 μg/L·min for 4 mg/kg to 305.616 mg/L·min for 12 mg/kg. After intragastrical (i.g.) dosing of 20 mg/kg, plasma levels of 10-dehydroxyl-12-demethoxy-conophylline peaked at about 90 min. 10-dehydroxyl-12-demethoxy-conophyllinea absolute oral bioavailability was only 15.79%. The pharmacokinetics process of the drug was fit to a two-room model. Following a single i.v. dose (8 mg/kg), 10-dehydroxyl-12-demethoxy-conophylline was detected in all examined tissues with the highest in kidney, liver, and lung. Equilibrium dialysis was used to evaluate plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline at three concentrations (1.00, 2.50, and 5.00 µg/mL). Results indicated a very high protein binding degree (over 80%), reducing substantially the free fraction of the compound.

Keywords: 10-dehydroxyl-12-demethoxy-conophylline; pharmacokinetics; protein binding rate; tissue distribution.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
Chemical structure of 10-dehydroxyl-12-demethoxy-conophylline.
Figure 2
Figure 2
Mean plasma concentration–time (mean ± SD) profiles of 10-dehydroxyl-12-demethoxyconophylline in rats after receiving a single intravenous (i.v.) dose at different concentration levels (4, 8, and 12 mg/kg, n = 6).
Figure 3
Figure 3
Mean plasma concentration–time (mean ± SD) profiles of 10-dehydroxyl-12-demethoxyconophylline following an intragastrical (i.g.) dose of 20 mg/kg in rats (n = 6).
Figure 4
Figure 4
Dose positive correlation of single dose (4, 8, and 12 mg/kg) AUC0→t (n = 6).
Figure 5
Figure 5
Concentration of 10-dehydroxyl-12-demethoxy-conophylline in rat tissues at 5, 20, and 45 min after receiving a single i.v. dose of 10-dehydroxyl-12-demethoxy-conophylline at 8 mg/kg (mean ± SD, n = 6).
Figure 6
Figure 6
Ratio of tissue-to-plasma concentrations (Kp) at 5, 20, and 45 min after receiving a single i.v. dose of 10-dehydroxyl-12-demethoxy-conophylline at 8 mg/kg (mean ± SD, n = 6).
Figure 7
Figure 7
Protein binding ratio of 10-dehydroxyl-12-demethoxy-conophylline in rat plasma.
Figure 8
Figure 8
Protein binding ratio of 10-dehydroxyl-12-demethoxy-conophylline in human plasma.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Ma H., Xie X., Jing P., Zhang W., She X. Concise total synthesis of (+/−)-aspidospermidine. Org. Biomol. Chem. 2015;13:5255–5259. doi: 10.1039/C5OB00228A. - DOI - PubMed
    1. Qu Y., Easson M., Simionescu R., Hajicek J., Thamm A.M.K., Salim V., De Luca V. Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine. Proc. Natl Acad. Sci. USA. 2018;115:3180–3185. doi: 10.1073/pnas.1719979115. - DOI - PMC - PubMed
    1. Kumar S.R., Shilpashree H.B., Nagegowda D.A. Terpene moiety enhancement by overexpression of geranyl(geranyl) diphosphate synthase and geraniol synthase elevates monomeric and dimeric monoterpene indole alkaloids in transgenic catharanthus roseus. Front. Plant Sci. 2018;9:942. doi: 10.3389/fpls.2018.00942. - DOI - PMC - PubMed
    1. Saxton J.E. Recent progress in the chemistry of the monoterpenoid indole alkaloids. Nat. Prod. Rep. 1995;12:385–411. doi: 10.1039/np9951200385. - DOI - PubMed
    1. Coatti G.C., Marcarini J.C., Sartori D., Fidelis Q.C., Ferreira D.T., Mantovani M.S. Cytotoxicity, genotoxicity and mechanism of action (via gene expression analysis) of the indole alkaloid aspidospermine (antiparasitic) extracted from Aspidosperma polyneuron in HepG2 cells. Cytotechnology. 2016;68:1161–1170. doi: 10.1007/s10616-015-9874-9. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources