Pharmacokinetics of d-limonene in the rat by GC–MS assay

Chen, Haitao; Chan, Kenneth K.; Budd, Thomas

doi:10.1016/s0731-7085(97)00243-4

Cited by 31 publications

(30 citation statements)

References 8 publications

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“…d-Limonene metabolite levels were not measured in this study. Another study demonstrated that, in rats, after oral administration of 200 mg/kg d-limonene, oral bioavailability was estimated to be 43% [63]. Thus, there is ample evidence supporting d-limonene's safety and bioavailability after oral consumption, making it well posed for development as a chemopreventive agent.…”

Section: D-limonene Tolerability and Dosing Studiesmentioning

confidence: 99%

d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment

et al. 2010

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Although limited, observations from cell culture, animal, and epidemiological studies support the presence of anti-cancer properties in citrus peel and the primary bioactive food constituent, d-limonene. Early evidence from animal models suggests that when ingested, d-limonene exhibits a wide spectrum of biologic activity including chemotherapeutic and chemopreventive effects. In some of these early models, an analog of d-limonene, perillyl alcohol, demonstrated a more potent effect than d-limonene itself. Yet, when perillyl alcohol advanced to clinical trials, several trials were ended early due to doselimiting toxicities. Alternatively, oral d-limonene administration in humans is well tolerated even at high doses supporting its investigation as a potential bioactive for cancer prevention. Though the exact mechanisms of action of d-limonene are unclear, immune modulation and antiproliferative effects are commonly reported. Here, we review the pre-clinical evidence for d-limonene's anticancer mechanisms, bioavailability, and safety, as well as the evidence for anti-cancer effects in humans, focusing on studies relevant to its use in the prevention and treatment of breast cancer.

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Section: D-limonene Tolerability and Dosing Studiesmentioning

confidence: 99%

d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment

et al. 2010

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“…The facile metabolism of terpene nitriles observed in our clearance experiments is consistent with results obtained by Diliberto et al (1988) with citral (3,7-dimethyl-2,6-octadienal), which was completely cleared from the plasma within 5 min after intravenous administration in rats. Likewise, metabolic clearance of limonene in rats is rapid, with a plasma half-life of approximately 12 min (Chen et al, 1998). Hepatocyte clearance of GN and CN was 2 to 5 times greater in mouse compared with rat.…”

Section: Discussionmentioning

confidence: 97%

Comparative Metabolism of Geranyl Nitrile and Citronellyl Nitrile in Mouse, Rat, and Human Hepatocytes

Kemper

Nabb²,

Gannon³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Geranyl nitrile (GN) and citronellyl nitrile (CN) are fragrance components used in consumer and personal care products. Differences in the clastogenicity of these two terpenes are postulated to result from differential biotransformation, presumably involving the conjugated nitrile moiety. The metabolic clearance and biotransformation of GN and CN were compared in primary hepatocytes from mice, rats, and humans. For determination of intrinsic clearance, GN and CN were incubated with hepatocytes in sealed vials, and the headspace was sampled periodically by solid-phase microextraction and analyzed by gas chromatography/mass spectrometry. For metabolite identification, GN and CN were incubated with hepatocytes from each species for 60 min, and reaction mixtures were extracted and analyzed by mass spectroscopy. Both GN and CN were rapidly metabolized in hepatocytes from all species (T 1/2 , 0.7-11.6 min). Within a species, intrinsic clearance was similar for both compounds and increased in the order human < rat Ͻ Ͻ mouse. Major common pathways for biotransformation of GN and CN involved 1) epoxidation of the 6-alkenyl moiety followed by conjugation with glutathione, 2) hydroxylation of the terminal methyl group(s) followed by direct conjugation with glucuronic acid in rodents or further oxidation to the corresponding acid in human cells, and 3) hydroxylation of the allylic C 5 position. No evidence for either phase I or phase II metabolism of the conjugated nitrile moiety was obtained. Thus, the presumed metabolic basis for differences in genotoxicity remains elusive.Geranyl nitrile (3,7-dimethyl-2,6-octadienenitrile, GN) and citronellyl nitrile (3,7-dimethyl-6-octenenitrile, CN) are monoterpene nitriles used extensively as fragrance ingredients (Fig. 1). Commercial GN consists of an isomeric mixture of geranyl nitrile (E isomer) and neryl nitrile (Z isomer). These compounds are common components in a wide variety of consumer products, including soaps, shampoos, cosmetics, perfumes, detergents, and insect repellents. In 1995 and 1996, 238 metric tons of GN and 45 metric tons of CN were used worldwide (Potter et al., 2001). The primary expected route of human exposure for both compounds is via dermal contact. However, there is also potential for oral exposure from detergent residues on dinnerware and for inhalation exposure via volatilization or aerosol formation. The extent of systemic bioavailability of these compounds by the various potential routes of human exposure has not been assessed.The acute toxicity of both nitriles is low, with oral LD 50 values in rats of approximately 3 g/kg for both compounds and dermal LD 50 values in rabbits of approximately 4 g/kg (RIFM, 1974a,b). The acute toxicity of geranyl nitrile is also low by the inhalation route, with a 4-h LC 50 greater than 5.2 mg/l [BASF (1989) Acute toxicity studies on geranyl nitrile and citronellyl nitrile (unpublished report)]. In a 28-day subchronic study, decreased body weight, minor changes in clinical chemistry and urinalysis parameters, ...

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“…Wang et al analyzed the concentration of DL in human plasma, but the preparation procedure was complex and multi‐step (Wang et al, ). Chen et al investigated the pharmacokinetics of DL in rat by GC–MS with a composited radioactive internal standard (Chen, Chan, & Budd, ). All of the above analytical methods were complicated or hazardous, with radioactive elements.…”

Section: Introductionmentioning

confidence: 99%

Determination of d‐limonene in mice plasma and tissues by a new GC–MS/MS method: Comparison of the pharmacokinetics and tissue distribution by oral and inhalation administration in mice

Chen

Sheng

et al. 2019

Biomedical Chromatography

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The aim of the present study was to develop a method based on gas chromatography–tandem mass spectrometry (GC–MS/MS) to determine and quantify the d‐limonene in mouse plasma and tissue samples. This new method was validated for the quantification of d‐limonene with the linearity ranges 1.0–1000.0 ng/mL (r2 > 0.9952) for plasma samples and 5.0–5000.0 ng/g (r2 > 0.9940) for tissue samples. The intra‐ and inter‐day assay of precisions in plasma and tissues were <13.4% and the accuracies were within 91.1–105.8%. In the oral/inhalation administration pharmacokinetics and tissue distribution studies, the main pharmacokinetic parameters were the peak concentration = (97.150 ± 34.450)/(4336.415 ± 1142.418) ng/mL, the area under the curve = (162.828± 27.447)/(2085.721 ± 547.787) h ng/mL and the half‐life = (3.196 ± 0.825)/(0.989 ± 0.095) h. The tissue distribution of d‐limonene in mice after oral/inhalation administration demonstrated a decreasing tendency in different tissues (liver > kidney > heart > lung > spleen).

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Pharmacokinetics of d-limonene in the rat by GC–MS assay

Cited by 31 publications

References 8 publications

d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment

d-Limonene: a bioactive food component from citrus and evidence for a potential role in breast cancer prevention and treatment

Comparative Metabolism of Geranyl Nitrile and Citronellyl Nitrile in Mouse, Rat, and Human Hepatocytes

Determination of d‐limonene in mice plasma and tissues by a new GC–MS/MS method: Comparison of the pharmacokinetics and tissue distribution by oral and inhalation administration in mice

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