Pharmacokinetic scaling of epirubicin using allometric and species-invariant time methods

Shin, Dae Hwan; Park, Seung Hyeok; Jeong, Sung Woo; Kwon, Oh‐Seung; Park, Chun‐Woong; Han, Ke; Chung, Youn Bok

doi:10.1007/s40005-015-0189-9

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…The femoral vein and artery of rats were cannulated with polyethylene tube (Becton Dickinson Diagnostics; MD, USA) 4 h before the administration of alantolactone, while the rats were anesthetized with zoletil (20 mg/kg, intramuscular injection) . Alantolactone was administered intravenously (10 mg/kg; dissolved in a vehicle composed of ethanol/PEG400/water [1:1:1, v/v/v]) or orally (50 mg/kg; dissolved in a vehicle composed of ethanol/PEG400 [70:30, v/v]) to rats.…”

Section: Methodsmentioning

confidence: 99%

High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

Lee

Kim

Chun

et al. 2016

Biopharm & Drug Disp

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Alantolactone (ALA) is a major bioactive sesquiterpene lactone present in the roots of Inula helenium L. (Asteraceae) which has been used widely in traditional medicine against various diseases such as asthma, cancer and tuberculosis. The pharmacologic activities of alantolactone have been well characterized, yet information on the physicochemical and pharmacokinetic properties of alantolactone and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of alantolactone and their relevant mechanisms. Log P values of alantolactone ranged from 1.52 to 1.84, and alantolactone was unstable in biological samples such as plasma, urine, bile, rat liver microsomes (RLM) and simulated gastrointestinal fluids. The metabolic rate of alantolactone was markedly higher in rat liver homogenates than in the other tissue homogenates. A saturable and concentration-dependent metabolic rate profile of alantolactone was observed in RLM, and rat cytochrome P450 (CYP) 1 A, 2C, 2D and 3 A subfamilies were significantly involved in its hepatic metabolism. Based on the well-stirred model, the hepatic extraction ratio (HER) was estimated to be 0.890-0.933, classifying alantolactone as a drug with high HER. Moreover, high total body clearance (111 ± 41 ml/min/kg) and low oral bioavailability (0.323%) of alantolactone were observed in rats. Taken together, the present study demonstrates that the extensive hepatic metabolism, at least partially mediated by CYP, is primarily responsible for the high total body clearance of alantolactone, and that the low oral bioavailability of alantolactone could be attributed to its low stability in gastrointestinal fluids and a hepatic first-pass effect in rats. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Methodsmentioning

confidence: 99%

High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

Lee

Kim

Chun

et al. 2016

Biopharm & Drug Disp

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Interspecies pharmacokinetic scaling of 11-hydroxyaclanomycin X based on animal data

신대환¹,

이소영²,

Woo³

et al. 2017

J Biomed Transl Res

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The pharmacokinetics of 11-Hydroxyaclacinomycin X (HAMX), a novel anthracycline, were investigated after intravenous bolus administration in mice, rats, rabbits and dogs. Based on animal data, we predicted the following human pharmacokinetic parameters using allometric scaling: 24.1 and 6.99 mL/min/kg for total body clearance (CLt) using simple and maximum lifespan potential (MLP)-corrected allometry, respectively; 5.72 L/kg for steady-state volume of distribution (Vdss). The corresponding allometric equation were CLt = 45.896W 0.8452 , CLt × MLP = 31.175W 1.1405 and Vdss = 10140x 0.8653. These allometric equations were extrapolated to predict CLt and Vdss in human based on 70 kg body weight. We also predicted human parameters using species-invariant time transformations (equivalent time, kallynochrons, apolysichrons and dienetichrons). The values of Vdss (15.4-19.4 L/kg) obtained using invariant time transformations were larger than those obtained using simple allometry. However, the lowest CLt (17.0 mL/min/kg) derived using dienetichrons was comparable to that obtained using simple allometry. The results of this study also indicated that the predicted human CLt generated using MLP-corrected allometry can be used for the selection of a safe dose for studies in healthy adult human volunteers. These results suggest that such approaches may be useful in designing pharmacokinetic studies for novel anthracyclines. The preliminary parameter values may be useful in designing early pharmacokinetic studies of HAMX in humans. The results could also be used to determine the safe dose for the therapeutics in various animals.

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Pharmacokinetic scaling of epirubicin using allometric and species-invariant time methods

Cited by 2 publications

References 22 publications

High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

Interspecies pharmacokinetic scaling of 11-hydroxyaclanomycin X based on animal data

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