Determination of ferruginol in rat plasma via high‐performance liquid chromatography and its application in pharmacokinetics study

Ferruginol, a diterpene phenol, has recently received attention for its extensive pharmacological properties, including anti‐tumor, antibacterial, cardio‐protective and gastroprotective effects. In the present study, a high‐performance liquid chromatographic (HPLC) method was developed for determination of ferruginol in rat plasma and applied for the pharmacokinetics study. The HPLC assay was performed with a VP ODS‐C₁₈ column. The mobile phaseconsisted of methanol and 1% acetic acid solution (90:10, v/v). The flow rate was 1.0 mL/min, and the wavelength was set at 270 nm. This method was linear over the studied range of 0.1–10.0 µg/mL for ferruginol. The correlation coefficient was 0.9998. The intra‐day and inter‐day precisions were better than 4 and 5%, respectively. The extraction recovery and accuracy were greater than 97 and 96%, respectively. The detection limit was 30 ng/mL. The mean maximum concentration of ferruginol in rat plasma was 3.14 µg/mL at 40 min after oral administration at a dose of 20 mg/kg. Ferruginol was absorbed quickly p.o. with t_1/2ka = 14.86 min and had a high rate of elimination with t_1/2 = 41.73 min. The pharmacokinetic process of ferruginol in rat was well described with a one‐compartment model. Copyright © 2009 John Wiley & Sons, Ltd.     

An ultra high performance liquid chromatography with tandem mass spectrometry method for simultaneous determination of thirteen components extracted from Radix Puerariae in rat plasma and tissues: Application to pharmacokinetic and tissue distribution study

A rapid and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for simultaneous determination of thirteen bioactive components (gallic acid, protocatechuic acid, puerarin, p‐hydroxycinnamic acid, daidzin, ononin, daidzein, naringenin, genistein, apigenin, formononetin, biochanin A, and β‐sitosterol) of Radix Puerariae extract in rat plasma and tissues. The plasma and tissues samples were pretreated by protein precipitation extraction, and umbelliferone and rutin were used as internal standards. Sample separation was performed on a ZORBAX RRHD Eclipse plus C₁₈ column (2.1 mm × 50 mm, 1.8 µm, Agilent) with a mobile phase consisting of methanol–water (containing 0.1% formic acid). The mass spectrometry analysis was conducted in positive and negative ionization modes with multiple reaction monitoring. The lower limit of quantitation range for the 13 analytes was 0.2?35 ng/mL. The intra‐ and inter‐day precision of all the analytes were less than 10.92%, with an accuracy ranging from ?13.10 to 11.96%. Both the recovery and matrix effect were within acceptable limits. This method was successfully applied to pharmacokinetic and tissue distribution study of the 13 bioactive components in rats after oral administration of R. Puerariae extract.     

Determination of a novel anticancer c‐Met inhibitor LS‐177 in rat plasma and tissues with a validated UPLC‐MS/MS method: application to pharmacokinetics and tissue distribution study

LS‐177 is a novel small‐molecule kinase inhibitor employed to interrupt the c‐Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated for determination of LS‐177 in rat plasma and tissues. The biosamples were extracted by liquid–liquid extraction with methyl tert‐butyl ether and separated on a C₁₈ column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile–0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from ?12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS‐177 was stable during the preparation and analytical processes. The UPLC‐MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple‐dose oral administration of LS‐177. The tissue distribution study exhibited significant higher uptakes of LS‐177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application. Copyright © 2014 John Wiley & Sons, Ltd.     

PEEK tube‐based online solid‐phase microextraction–high‐performance liquid chromatography for the determination of yohimbine in rat plasma and its application in pharmacokinetics study

Yohimbine is a novel compound for the treatment of erectile dysfunction derived from natural products, and pharmacokinetic study is important for its further development as a new medicine. In this work, we developed a novel PEEK tube‐based solid‐phase microextraction (SPME)–HPLC method for analysis of yohimbine in plasma and further for pharmacokinetic study. Poly (AA‐EGDMA) was synthesized inside a PEEK tube as the sorbent for microextraction of yohimbine, and parameters that could influence extraction efficiency were systematically investigated. Under optimum conditions, the PEEK tube‐based SPME method exhibits excellent enrichment efficiency towards yohimbine. By using berberine as internal standard, an online SPME‐HPLC method was developed for analysis of yohimbine in human plasma sample. The method has wide linear range (2–1000 ng/mL) with an R ² of 0.9962; the limit of detection was determined and was as low as 0.1 ng/mL using UV detection. Finally, a pharmacokinetic study of yohimbine was carried out by the online SPME‐HPLC method and the results have been compared with those of reported methods.     

Development and validation of a sensitive quantification method for hematoporphyrin monomethyl ether in plasma using high-performance liquid chromatography with fluorescence detection

A rapid, sensitive, precise and specific method for determination of hematoporphyrin monomethyl ether (HMME), a novel photodynamic therapy (PDT) drug, was developed and validated using high-performance liquid chromatography (HPLC) with fluorescence detection. HMME was isolated from the plasma by a single-step liquid-liquid extraction with ethyl acetate. The analyte and internal standard fluorescein were baseline separated on a Diamonsil C(18) analytical column (4.6 x 150 mm, 5 microm) and analyzed using a fluorescence detector with the excitation and emission wavelengths set at 395 and 613 nm, respectively. The method was linear in the concentration range 0.025-5 microg/mL with a lower limit of quantitation (LLOQ) of 10 ng/mL. The inter- and intra-day accuracies and precisions were all within 10% and the mean recoveries of HMME and fluorescein were 95 +/- 3.7 and 90 +/- 2.3%, respectively. The analyte was stable during all sample storage, preparation and analysis periods. This method was successfully applied to a pharmacokinetic study after a single-dose intravenous administration of HMME (5 mg/kg) to beagle dogs. This method was reproducible and sensitive enough for the pharmacokinetic study of HMME. Based on the results of the pharmacokinetic study, we suggest that a rather long light-avoiding time is essential for patients under HMME therapy.     

A rapid and sensitive LC‐MS/MS method for the determination of linarin in small‐volume rat plasma and tissue samples and its application to pharmacokinetic and tissue distribution study

A rapid and sensitive LC‐MS/MS method was developed for the determination of linarin in small‐volume rat plasma and tissue sample. Sample preparation was employed by the combination of protein precipitation (PPT) and liquid–liquid extraction (LLE) to allow measurement over a 5‐order‐of‐magnitude concentration range. Fast chromatographic separation was achieved on a Hypersil Gold column (100 × 2.1 mm i.d., 5 µm). Mass spectrometric detection was achieved using a triple‐quadrupole mass spectrometer equipped with an electrospray ionization interface operating in positive ionization mode. Quantification was performed using selected reaction monitoring of precursor‐product ion transitions at m/z 593 → 285 for linarin and m/z 447 → 271 for baicalin (internal standard). The total run time was only 2.8 min per sample. The calibration curves were linear over the concentration range of 0.4–200 µg/mL for PPT and 0.001–1.0 µg/mL for LLE. A lower limit of quantification of 1.0 ng/mL was achieved using only 20 μL of plasma or tissue homogenate. The intra‐ and inter‐day precisions in all samples were ≤14.7%, while the accuracy was within ±5.2% of nominal values. The validated method has been successfully applied to pharmacokinetic and tissue distribution study of linarin. Copyright © 2015 John Wiley & Sons, Ltd.     

A novel UPLC‐MS/MS method for sensitive quantitation of boldine in plasma,a potential anti‐inflammatory agent: application to a pharmacokinetic study in rats

Boldine is a potential anti‐inflammatory agent found in several different plants. Published bioanalytical methods using HPLC with ultraviolet and fluorescent detection lacked enough sensitivity and required tedious sample preparation procedures. Herein, we describe the development of a novel ultra‐high performance LC with MS/MS for determination of boldine in plasma. Boldine in plasma was recovered by liquid–liquid extraction using 1 mL of methyl tert‐butyl ether. Chromatographic separation was performed on a C₁₈ column at 45°C, with a gradient elution consisting of acetonitrile and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The detection was performed on an electrospray triple‐quadrupole MS/MS by positive ion multiple reaction monitoring mode. Good linearity (r² > 0.9926) was achieved in a concentration range of 2.555–2555 ng/mL with a lower limit of quantification of 2.555 ng/mL for boldine. The intra‐ and inter‐day precisions of the assay were 1.2–6.0 and 1.8–7.4% relative standard deviation with an accuracy of ?6.0–8.0% relative error. This newly developed method was successfully applied to a single low‐dose pharmacokinetic study in rats and was demonstrated to be simpler and more sensitive than the published methods, allowing boldine quantification in reduced plasma volume. Copyright © 2014 John Wiley & Sons, Ltd.     

UHPLC‐MS method for determination of gambogic acid and application to bioavailability,pharmacokinetics, excretion and tissue distribution in rats

A sensitive ultrahigh performance liquid chromatography tandem mass spectrometry (UHPLC‐MS) method was developed for determination of gambogic acid (GA) in rat plasma, urine, bile and main tissues. GA was separated on an Agilent Zorbax XDB–C₁₈ column (50 × 2.1 mm, 1.8 µm) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by negative electrospray ionization with multiple reaction monitoring mode. The calibration curves of GA were linear between 1.0 and 1000 ng/mL in rat plasma and bile and between 1.0 and 500 ng/mL in urine and tissues. The lowest limit of quantification for all matrices was 1.0 ng/mL. Both accuracy and precision of the assay were satisfactory. This validated method was firstly applied to bioavailability (BA), pharmacokinetics, excretion and tissue distribution in rats. The BAs of GA (40 and 80 mg/kg) in rats were 0.25 and 0.32%, respectively. GA was distributed extensively in rats after oral administration and exhibited the highest level in liver. GA reached the cumulative excretion amount of 25.3 ± 1.7 µg in bile and 0.275 ± 0.08 µg in urine after i.g. 80 mg/kg to rats at 24 h. The present results would be helpful for further clinical use of GA as a potential anticancer drug. Copyright © 2015 John Wiley & Sons, Ltd.     

Interaction study of acetylcholinestrase inhibitors on pharmacokinetics of memantine in rat plasma by HPLC‐fluorescence method

The present study aims to investigate the possibility of interaction of donepezil (DP) and galantamine (GAL) as acetylcholinestrase inhibitors, on memantine (MT) hydrochloride in rat plasma by HPLC‐fluorescence detection. The separation of MT was achieved within 12 min without interference of DP and GAL on the chromatogram. MT levels in rat plasma with a single administration of MT (2.5 mg/kg, i.p.) and those with a co‐administration of DP (5.0 mg/kg, i.p.) and GAL (3 mg/kg, i.p.) were monitored. MT concentrations determined in rat plasma ranged from 10.0 to 245.6 ng/mL. Significant difference was observed in the behavior of MT with a co‐administration of DP, while no significant difference was observed with a co‐administration of GAL. Copyright © 2013 John Wiley & Sons, Ltd.     

3‐(2‐Bromoacetamido)‐N‐(9‐ethyl‐9H)‐carbazol fluorescent probe and its application for the determination of thiophenols in rubber products by HPLC with fluorescence detection and atmospheric chemical ionization mass spectrometry identification

A rapid, sensitive, and selective precolumn derivatization method for the simultaneous determination of eight thiophenols using 3‐(2‐bromoacetamido)‐N‐(9‐ethyl‐9H )‐carbazol as a labeling reagent by high‐performance liquid chromatography with fluorescence detection has been developed. The labeling reagent reacted with thiophenols at 50°C for 50 min in aqueous acetonitrile in the presence of borate buffer (0.10 mol/L, pH 11.2) to give high yields of thiophenol derivatives. The derivatives were identified by online postcolumn mass spectrometry. The collision‐induced dissociation spectra for thiophenol derivatives gave the corresponding specific fragment ions at m/z 251.3, 223.3, 210.9, 195.8, and 181.9. At the same time, derivatives exhibited intense fluorescence with an excitation maximum at λ_ex = 276 nm and an emission maximum at λ_em = 385 nm. Excellent linear responses were observed for all analytes over the range of 0.033–6.66 μmol/L with correlation coefficients of more than 0.9997. Detection limits were in the range of 0.94–5.77 μg/L with relative standard deviations of less than 4.54%. The feasibility of derivatization allowed the development of a rapid and highly sensitive method for the quantitative analysis of trace levels of thiophenols from some rubber products. The average recoveries (n = 3) were in the range of 87.21–101.12%.     

Improved HPLC method for doxorubicin quantification in rat plasma to study the pharmacokinetics of micelle-encapsulated and liposome-encapsulated doxorubicin formulations

An improved simple, rapid and accurate HPLC method for quantification of doxorubicin derived from micelle-encapsulated or liposome-encapsulated doxorubicin formulation in rat plasma was described. The mobile phase consisting of a mixture of methanol-water [containing 0.1% formic acid anhydrous and 0.1% ammonia solution (25%), pH 3.0], 60:40, was delivered at a flow rate of 1.0 mL/min. Sample preparation for micelle- or liposome-encapsulated doxorubicin in rat plasma were achieved directly by protein precipitation with acetonitrile. Doxorubicin and daunorubicin (internal standard, IS) were separated on a C(18) reversed-phase HPLC column and quantified by a fluoresence detection with an excitation wavelength of 475 nm and an emission wavelength of 580 nm. The linearity was obtained over the range of 5.0-1000.0 ng/mL and 1.0-200.0 microg/mL for doxorubicin and the lower limit of quantitation was 5.0 ng/mL. For each level of quality control samples, inter- and intra-assay precision was less than 9.6 and 5.1% (relative standard deviation), respectively, and percentage error was within +/-2.6%. The extraction recoveries of doxorubicin in the range of 10 ng/mL to 100 microg/mL in rat plasma were between 94.1 and 105.6%. This method was successfully applied to the pharmacokinetic study of doxorubicin formulations after i.v. administration to rats.     

Rapid and sensitive LC‐MS method for pharmacokinetic study of vinorelbine in rats

A rapid and sensitive LC‐electrospray ionization‐MS method was developed for determining vinorelbine in rat plasma. A 100 µL plasma sample was treated using a protein precipitation procedure and was chromatographed within 4 min using an Inertsil ODS‐3 C₁₈ (2.1 × 50 mm, 5 µm) column. The selected ion monitoring ions [M + H]⁺ were m/z 779 and m/z 811 for vinorelbine and vinblastine (internal standard), respectively. The method validation showed that the calibration curve for vinorelbine was linear over a concentration range of 1–1000 ng/mL with lower limit of quantification at 1 ng/mL. The method has been successfully applied to pharmacokinetics in rat plasma. Copyright © 2009 John Wiley & Sons, Ltd.     

Quantitative determination of periplocymarin in rat plasma and tissue by LC‐MS/MS: application to pharmacokinetic and tissue distribution study

A simple, rapid and sensitive liquid chromatography with tandem mass spectrometry (LC‐MS/MS) method for the determination of periplocymarin in biological samples was developed and successfully applied to the pharmacokinetic and tissue distribution study of periplocymarin after oral administration of periplocin. Biological samples were processed with ethyl acetate by liquid–liquid extraction, and diazepam was used as the internal standard. Periplocymarin was analyzed on a C₁₈ column with isocratic eluted mobile phase composed of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min (73:27, v/v). Detection was performed on a triple‐quadrupole tandem mass spectrometer using positive‐ion mode electrospray ionization in the selected reaction monitoring mode. The MS/MS ion transitions monitored were m/z 535.3→355.1 and 285.1→193.0 for periplocymarin and diazepam, respectively. Good linearity was observed over the concentration ranges. The lower limit of quantification was 0.5 ng/mL in plasma and tested tissues. The intra‐and inter‐day precisions (relative standard deviation) were <10.2 and 10.5%, respectively, and accuracies (relative error) were between ?6.8 and 8.9%. Recoveries in plasma and tissue were >90%. The validated method was successfully applied to the pharmacokinetic and tissue distribution studies of periplocymarin in rats. Copyright © 2016 John Wiley & Sons, Ltd.     

Preparation,antitumor activity in mice,pharmacokinetics and tissue distribution in rats of di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) liposome

Di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) (DBDCT) is an antitumor compound with high activity and relatively low bioavailability. In order to improve the pharmacokinetic characteristics and raise its therapeutic index, a liposome of DBDCT (DBDCT‐L) was prepared for the first time. A study of the pharmacokinetics and tissue distribution after intravenous administration of DBDCT‐L compared with free DBDCT to rats was investigated. DBDCT‐L showed a slower clearance, increased half‐time and a larger AUC value than those of free DBDCT, which demonstrated that DBDCT‐L could significantly alter the tissue distribution pattern of DBDCT in rats. The highest concentration distribution for DBDCT‐L was detected in liver, which may be associated with the enhanced antitumor activity in vivo against hepatocellular carcinoma H₂₂ and possible target release of the compound. Acute toxicity assay showed that the LD₅₀ value of DBDCT‐L was higher than that of free DBDCT. Further in vivo antitumor test showed that DBDCT‐L displayed higher antitumor activity against the hepatocellular carcinoma H₂₂ than free DBDCT, indicating that the liposome could prolong the action time of DBDCT in the system circulation, change its distribution in rats, reduce acute toxicity and finally increase antitumor activity. Copyright © 2014 John Wiley & Sons, Ltd.     

Pharmacokinetics,tissue distribution,and excretion studies of l‐isocorypalmine using ultra high performance liquid chromatography with tandem mass spectrometry

l ‐Isocorypalmine is a newly identified metabolite of l ‐tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l ‐isocorypalmine in Sprague–Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l ‐isocorypalmine in biological samples. The biological samples were extracted by liquid–liquid extraction and separated on a Bonshell ASB C₁₈ column (2.1 × 100 mm, 2.7 μm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l ‐isocorypalmine. The results showed that l ‐isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5–15 mg/kg. In addition, the results would be helpful for further clinical reference of l ‐isocorypalmine as a potential candidate drug for the treatment of cocaine addiction.     

Determination of picroside II in dog plasma by HPLC and its application in a pharmacokinetics study

A sensitive and simple high-performance liquid chromatography method with UV detection was developed and validated for determining picroside II in dog plasma. Paeoniflorin was employed as internal standard and the sample pre-treatment procedure consists of deproteinization by addition of acetonitrile. Chromatographic separations were performed on a Shimadzu VP-ODS column (250 x 4.6 mm i.d., 5 microm). The mobile phase consisted of acetonitrile-0.1% acetic acid aqueous (v/v), 23:77, v/v, at a rate of 1 mL/min. Detection was carried out at a wavelength of 266 nm. Calibration standards ranged from 0.25 to 500 microg/mL in dog plasma and the mean correlation coefficient of 0.9981 was found for the linear calibration curves (n = 6). The limit of quantification (LOQ) was 0.25 microg/mL. Intra- and inter-assay RSD ranged from 0.70 to 7.5%. Accuracy (%bias) ranged from -6.3 to 6.0%. This method was applied to the pharmacokinetic study of picroside II in dogs. The study demonstrated the plasma picroside II concentration-time curves were fitted to the two-compartment open model and showed linear pharmacokinetics.     

Ultra‐high‐performance liquid chromatography–tandem mass spectrometry for pharmacokinetics of bakuchiol in rats

Psoralea Corylifolia L. is a traditional Chinese medicine with many beneficial effects in medical therapies. Bakuchiol was the main active ingredient of Psoralea Corylifolia L., used for the treatment of various diseases and also as a natural food additive. A specific and reliable ultra‐high performance liquid chromatography–tandem mass spectrometry has been developed and fully validated for the quantification of bakuchiol in rat plasma. Chromatographic separation of bakuchiol and an internal standard, daidzein, was achieved on a Hypersil Gold C₁₈ column with gradient elution that consisted of methanol and water at a flow rate of 0.2 mL/min. The compounds were detected at negative ionization mode using mass transition m/z 255.2 → 172.0 and 252.9 → 132.0 for bakuchiol and daidzein, respectively. Good linearity was obtained over the range of 2–1000 ng/mL and the lower limit of quantification was 2 ng/mL. The intra‐ and inter‐day accuracies ranged from 91.1 to 105.7% and precisions (relative standard deviations) were within 9.3%. Bakuchiol was found to be stable under three freeze–thaw cycles, short‐term temperature, post‐preparative and long‐term temperature conditions. The method was applied to a pharmacokinetic study of bakuchiol intravenously administered to rats at a dose of 5 mg/kg. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetics and metabolism of olerciamide A from Portulaca oleracea L. in rats by UHPLC‐UV and UHPLC‐ESI‐Q‐TOF/MS

The aim of this study was to elucidate the pharmacokinetics of olerciamide A in rats after oral and intravenous administration of Portulaca oleracea L. extract by a simple and rapid ultra high‐performance liquid chromatography method with bergapten as internal standard. The pharmacokinetic results indicated that olerciamide A was rapidly distributed with a time to peak concentration of 30 min after oral administration and presented a low oral absolute bioavailability of 4.57%. The metabolism of olerciamide A in rats was also investigated using ultra‐high‐performance liquid chromatography electrospray coupled with quadrupole–time of flight mass spectrometry to elucidate the reason for the low absolute bioavailability of olerciamide A and seven metabolites of oleraciamide A were found in rat plasma and urine.     

Ethylene polymerization reactions with multicenter Ziegler‐Natta catalysts—Manipulation of active center distribution

This article describes ethylene/1‐hexene copolymerization reactions with a supported titanium‐based, multicenter Ziegler‐Natta catalyst. The catalyst was modified by pretreating its solid precursor with AlEt₂Cl and with similar organoaluminum chlorides, Al₂Et₃Cl₃, AlEtCl₂, and AlMe₂Cl. Testing of the untreated and the pretreated catalysts in copolymerization reactions under standard reaction conditions demonstrated that the modifying agents produce two changes in the catalyst. First, the pretreatment significantly reduces the reactivity of active centers that produce high molecular weight, highly crystalline copolymer components with a low 1‐hexene content. Second, the pretreatment noticeably increases the reactivity of active centers that produce low molecular weight copolymer components with a high 1‐hexene content. The first effect is caused by Lewis acid‐base interactions of the modifiers with the active centers, whereas the second (activating) effect is due to the removal of catalyst poisons (organosilicon compounds generated in the process of the catalyst synthesis) by AlEt₂Cl. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 4219–4229, 2010     

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

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).