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Development of physiologically based pharmacokinetic model of di-butyl phthalate and its toxic metabolite mono-butyl phthalate in rats
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S27eS107
P224 DEGLYCOSYLATION AND ABSORPTION OF MAREIN, FLAVANOMAREIN AND TAXIFOLIN-7-O-GLUCOPYRANOSIDE FROM CAPITULA OF COREOPSIS TINCTORIA IN RAT AND HUMAN Haixia Han 1, 2, Zhiyuan Ma 1, Wei Wang 1, Mingcheng Xu 1, Sisi Zhou 1, Liping Li 1, Huidi Jiang 1. 1 Zhejiang University, Hangzhou, China; 2 Xinjiang Agricultural University, Urumchi, China Marein, flavanomarein and taxifolin-7-O-b-D-glucopyranoside (TDG) are active components in capitula of C. tinctoria (CCT), however their absorptions are unclear yet. The present study was to elucidate their deglycosylation and absorption of in gastrointestinal tracts (GIT) of rat and human. The in vitro study showed marein, flavanomarein and TDG were deglycosylated to okanin, isookanin and taxifolin, respectively, in rat and human small intestine (duodenum, ileum, jejunum) and human colon, but not in other segements of GIT. Okanin and isookanin mainly in the form of glucuronide conjugate, whereas taxifolin was in sulfate in rat and human plasma. The mean plasma concentration-time profiles of rats after oral dose of CCT extract revealed the absorption was rapid with the Tmax less than 30 min. At the dosage of 200mg/kg, the Cmax of okanin, isookanin, taxifolin was 1554 ± 485, 388.9 ± 241 and 264.9 ± 95 ng/mL, while of marein, flavanomarein, TDG was 114.2 ± 30, 56.81 ± 20 and 73.53 ± 19 ng/ mL, respectively. The exposure (AUC) was positively correlated with the dosage of 100 to 400mg/kg. Marein, flavanomarein and TDG were not detected after intake of CCT (2.5 g/50 kg) water solution in human. While the concentration of okanin, isookanin, taxifolin at 0.75 h after dose was 2022 ± 491, 66.94 ± 42 and 22.55 ± 11 ng/mL, respectively, which were higher than that of 0.334, 1.5 and 4.0 h. The results showed the major part of marein, flavanomarein and TDG were deglycosylated to okanin, isookanin and taxifolin in rat and human GIT, which could be absorbed and subsequently to form glucuronide or sulfate conjugates. The results will help us to elucidate and explore the healthful activities of CCT. P225 DETERMINATION OF PHARMACOKINETICS OF FISETIN AND ITS MAIN METABOLITE IN MOUSE PLASMA BY LCeMS/MS Junhyeon Jo, Sangkyu Lee. BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea Fisetin(3,3’,4’,7-tetrahydroxyflavone) is a flavonoid found in several fruits, vegetables, nuts and wine. Fisetin have antioxidant and anti-inflammatory activities, and show the cytotoxic and antiangiogenic effect in vitro. Geraldol is 3’-methoxylated metabolite of fisetin (3,4’,7-trihydroxy-3’methoxyflavone) as a major metabolite of fisetin. In the present study, we developed and validated a quantification method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which was applied to a pharmacokinetic investigation in mouse plasma. LC was performed using an ACE 5 C18 column, and a mixture of acetonitrile and water containing 0.1% formic acid was used as the mobile phase at a flow rate of 220 uL/min. Transition ions of fisetin and geraldol in multiple reaction-monitoring modes using positive ionization were observed at m/z 287.1 to m/z 137.1 and m/z 301.2 to m/z 286.2, respectively. Fisetin, geraldol and the internal standard (terfenadine) eluted at retention times of 3.4, 3.5 and 3.6 min, respectively. The acceptable linearity (r2 ¼ 0.999 and 0.998) of fisetin and geraldol were observed over the concentration range of 20e15,000 ng/mL, with a lower quantification limit of 20 ng/mL in mouse plasma. This method was successfully applied to determine the pharmacokinetic parameters of fisetin and geraldol, its main metabolite, in mouse plasma. P226 DEVELOPMENT OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL OF DI-BUTYL PHTHALATE AND ITS TOXIC METABOLITE MONO-BUTYL PHTHALATE IN RATS Tae Hwan Kim, Min Gi Kim, Hyeon Gwan Choi, Youngsung Lee, Sungwook Park, Junwoo Park, Sun Dong Yoo. Sungkyunkwan University, Suwon, South Korea
S91
Di-butyl phthalate (DBP) is a plasticizer commonly used in the manufacture of various foamed poly vinyl chlorides. DBP is classified as a developmental toxicant, and its metabolites including mono-butyl phthalate (MBuP) are also shown to cause developmental and reproductive toxicities. This study was performed to develop a physiologically based pharmacokinetic (PBPK) model for MBuP which is linked with its parent compound, DBP. The PBPK model consisted of the MBuP and DBP components linked to each other via GI compartment where the metabolic conversion of DBP to MBuP takes place after oral exposure of DBP. Relevant pharmacokinetic studies were performed in rats, and the MBuP-specific parameters were estimated by fitting the blood and urine concentration vs. time profiles observed after intravenous injection and oral administration of each of these compounds. The tissue-to-blood partition coefficients of MBuP were determined for liver, kidney, testis and adipose under steadystate conditions after continuous intravenous infusion of MBuP in rats at a rate of 0.235 mg/kg/hr over a 24 hr period. The developed PBPK model was scaled to a human model by refining the parameters based on human physiological data. The model predictions were in good agreement with the observed data, indicating that the disposition of MBuP was adequately described by the developed model. Simulations of the MBuP concentrations in blood and tissues and the evaluation of the external dosimetry in humans will be further discussed. P227 EFFECTS OF COMPATIBILITY OF RADIX ACONITI CARMICHAELI AND PINELIA TERNATE ON PHARMACOKINETIC OF 9 ACONITUM ALKALOIDS IN NORMAL AND MODEL RAT PLASMA Ya Zhao 1, Rui Zhi Zhao 2. 1 Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China; 2 Guangdong Province Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China Radix aconiti carmichaeli (Fuzi in Chinese) and Pinellia ternate (Banxia in Chinese) are clinically common used traditional Chinese medicine. They both have toxicological risk and may be more serious when they used together, but the combination usage of the two medicines existed in Chinese Traditional Compound for two thousand years. The results of previous study were also controversial and the interaction mechanism of two herbs was worthy to investigate. The effect or toxicity of poisonous Traditional Chinese Medicine are some related to the property of Chinese traditional medicine, and some related to human body status. Investigating the effect or toxicity of Chinese Traditional medicine under the physiology body status or the pathologic body status could obtain obviously different results. So this paper was designed to investigate the influence of Pinellia ternate on pharmacokinetics of 9 Aconitum alkaloids in normal rat and model rat plasma to clarify the underlying interaction mechanism of two herbs and study the relations between the toxicity of Chinese herbal medicine and body function.The model rats were induced by intraperitoneally injecting hydrocortisone for 21 days. Then the normal rats and model rats were randomly divided into four groups and orally administered with Fuzi and Fuzi-Banxia aqueous extract. The concentrations of the Aconitum alkaloids in rat plasma were determined by UPLC-MS/MS, and main pharmacokinetic parameters were calculated by DAS2.0 software. The results showed that comparing with normal rats treated with Fuzi, AUC0t, of 9 Aconitum alkaloids increased by 26.3%, 114.3%, 90.2%, 58.7% ,85.7%, 117.8%,92.3%,60.2% and18.7% respectively, Cmax of benzoylaconine, benzoylhypaconine, benzoylmesaconine, aconine, hypaconine, mesaconine and fuziline increased by 66.4%, 60.1%, 141.1%,81.2%, 103.5%,67.1% and 12.4% (p<0.01, p<0.05 ). However comparing with model rats treated with Fuzi, the change of AUC, Cmax were not significant, T1/2 of hypaconine increased 66.1% (p<0.05), conversely, T1/2 of benzoylmesaconine decreased 45.1% (p<0.05). AUC0t and Cmax of Aconitum alkaloids in model rats treated with Fuzi decreased significantly(p<0.01, p<0.05 ), while T1/2 of them notably increased when compared with normal rats treated with Fuzi. The parameters were the same trend in model rats treated with Fuzi-Banxia comparing with accordingly normal group.These results indicated that Banxia could enhance the absorption of Aconitum alkaloids and promote their elimination in normal rats, but had no effect on the absorption of Aconitum alkaloids in model rats. The results also indicated that the absorption of Aconitum alkaloids reduced and their
P224 DEGLYCOSYLATION AND ABSORPTION OF MAREIN, FLAVANOMAREIN AND TAXIFOLIN-7-O-GLUCOPYRANOSIDE FROM CAPITULA OF COREOPSIS TINCTORIA IN RAT AND HUMAN Haixia Han 1, 2, Zhiyuan Ma 1, Wei Wang 1, Mingcheng Xu 1, Sisi Zhou 1, Liping Li 1, Huidi Jiang 1. 1 Zhejiang University, Hangzhou, China; 2 Xinjiang Agricultural University, Urumchi, China Marein, flavanomarein and taxifolin-7-O-b-D-glucopyranoside (TDG) are active components in capitula of C. tinctoria (CCT), however their absorptions are unclear yet. The present study was to elucidate their deglycosylation and absorption of in gastrointestinal tracts (GIT) of rat and human. The in vitro study showed marein, flavanomarein and TDG were deglycosylated to okanin, isookanin and taxifolin, respectively, in rat and human small intestine (duodenum, ileum, jejunum) and human colon, but not in other segements of GIT. Okanin and isookanin mainly in the form of glucuronide conjugate, whereas taxifolin was in sulfate in rat and human plasma. The mean plasma concentration-time profiles of rats after oral dose of CCT extract revealed the absorption was rapid with the Tmax less than 30 min. At the dosage of 200mg/kg, the Cmax of okanin, isookanin, taxifolin was 1554 ± 485, 388.9 ± 241 and 264.9 ± 95 ng/mL, while of marein, flavanomarein, TDG was 114.2 ± 30, 56.81 ± 20 and 73.53 ± 19 ng/ mL, respectively. The exposure (AUC) was positively correlated with the dosage of 100 to 400mg/kg. Marein, flavanomarein and TDG were not detected after intake of CCT (2.5 g/50 kg) water solution in human. While the concentration of okanin, isookanin, taxifolin at 0.75 h after dose was 2022 ± 491, 66.94 ± 42 and 22.55 ± 11 ng/mL, respectively, which were higher than that of 0.334, 1.5 and 4.0 h. The results showed the major part of marein, flavanomarein and TDG were deglycosylated to okanin, isookanin and taxifolin in rat and human GIT, which could be absorbed and subsequently to form glucuronide or sulfate conjugates. The results will help us to elucidate and explore the healthful activities of CCT. P225 DETERMINATION OF PHARMACOKINETICS OF FISETIN AND ITS MAIN METABOLITE IN MOUSE PLASMA BY LCeMS/MS Junhyeon Jo, Sangkyu Lee. BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea Fisetin(3,3’,4’,7-tetrahydroxyflavone) is a flavonoid found in several fruits, vegetables, nuts and wine. Fisetin have antioxidant and anti-inflammatory activities, and show the cytotoxic and antiangiogenic effect in vitro. Geraldol is 3’-methoxylated metabolite of fisetin (3,4’,7-trihydroxy-3’methoxyflavone) as a major metabolite of fisetin. In the present study, we developed and validated a quantification method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which was applied to a pharmacokinetic investigation in mouse plasma. LC was performed using an ACE 5 C18 column, and a mixture of acetonitrile and water containing 0.1% formic acid was used as the mobile phase at a flow rate of 220 uL/min. Transition ions of fisetin and geraldol in multiple reaction-monitoring modes using positive ionization were observed at m/z 287.1 to m/z 137.1 and m/z 301.2 to m/z 286.2, respectively. Fisetin, geraldol and the internal standard (terfenadine) eluted at retention times of 3.4, 3.5 and 3.6 min, respectively. The acceptable linearity (r2 ¼ 0.999 and 0.998) of fisetin and geraldol were observed over the concentration range of 20e15,000 ng/mL, with a lower quantification limit of 20 ng/mL in mouse plasma. This method was successfully applied to determine the pharmacokinetic parameters of fisetin and geraldol, its main metabolite, in mouse plasma. P226 DEVELOPMENT OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL OF DI-BUTYL PHTHALATE AND ITS TOXIC METABOLITE MONO-BUTYL PHTHALATE IN RATS Tae Hwan Kim, Min Gi Kim, Hyeon Gwan Choi, Youngsung Lee, Sungwook Park, Junwoo Park, Sun Dong Yoo. Sungkyunkwan University, Suwon, South Korea
S91
Di-butyl phthalate (DBP) is a plasticizer commonly used in the manufacture of various foamed poly vinyl chlorides. DBP is classified as a developmental toxicant, and its metabolites including mono-butyl phthalate (MBuP) are also shown to cause developmental and reproductive toxicities. This study was performed to develop a physiologically based pharmacokinetic (PBPK) model for MBuP which is linked with its parent compound, DBP. The PBPK model consisted of the MBuP and DBP components linked to each other via GI compartment where the metabolic conversion of DBP to MBuP takes place after oral exposure of DBP. Relevant pharmacokinetic studies were performed in rats, and the MBuP-specific parameters were estimated by fitting the blood and urine concentration vs. time profiles observed after intravenous injection and oral administration of each of these compounds. The tissue-to-blood partition coefficients of MBuP were determined for liver, kidney, testis and adipose under steadystate conditions after continuous intravenous infusion of MBuP in rats at a rate of 0.235 mg/kg/hr over a 24 hr period. The developed PBPK model was scaled to a human model by refining the parameters based on human physiological data. The model predictions were in good agreement with the observed data, indicating that the disposition of MBuP was adequately described by the developed model. Simulations of the MBuP concentrations in blood and tissues and the evaluation of the external dosimetry in humans will be further discussed. P227 EFFECTS OF COMPATIBILITY OF RADIX ACONITI CARMICHAELI AND PINELIA TERNATE ON PHARMACOKINETIC OF 9 ACONITUM ALKALOIDS IN NORMAL AND MODEL RAT PLASMA Ya Zhao 1, Rui Zhi Zhao 2. 1 Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China; 2 Guangdong Province Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China Radix aconiti carmichaeli (Fuzi in Chinese) and Pinellia ternate (Banxia in Chinese) are clinically common used traditional Chinese medicine. They both have toxicological risk and may be more serious when they used together, but the combination usage of the two medicines existed in Chinese Traditional Compound for two thousand years. The results of previous study were also controversial and the interaction mechanism of two herbs was worthy to investigate. The effect or toxicity of poisonous Traditional Chinese Medicine are some related to the property of Chinese traditional medicine, and some related to human body status. Investigating the effect or toxicity of Chinese Traditional medicine under the physiology body status or the pathologic body status could obtain obviously different results. So this paper was designed to investigate the influence of Pinellia ternate on pharmacokinetics of 9 Aconitum alkaloids in normal rat and model rat plasma to clarify the underlying interaction mechanism of two herbs and study the relations between the toxicity of Chinese herbal medicine and body function.The model rats were induced by intraperitoneally injecting hydrocortisone for 21 days. Then the normal rats and model rats were randomly divided into four groups and orally administered with Fuzi and Fuzi-Banxia aqueous extract. The concentrations of the Aconitum alkaloids in rat plasma were determined by UPLC-MS/MS, and main pharmacokinetic parameters were calculated by DAS2.0 software. The results showed that comparing with normal rats treated with Fuzi, AUC0t, of 9 Aconitum alkaloids increased by 26.3%, 114.3%, 90.2%, 58.7% ,85.7%, 117.8%,92.3%,60.2% and18.7% respectively, Cmax of benzoylaconine, benzoylhypaconine, benzoylmesaconine, aconine, hypaconine, mesaconine and fuziline increased by 66.4%, 60.1%, 141.1%,81.2%, 103.5%,67.1% and 12.4% (p<0.01, p<0.05 ). However comparing with model rats treated with Fuzi, the change of AUC, Cmax were not significant, T1/2 of hypaconine increased 66.1% (p<0.05), conversely, T1/2 of benzoylmesaconine decreased 45.1% (p<0.05). AUC0t and Cmax of Aconitum alkaloids in model rats treated with Fuzi decreased significantly(p<0.01, p<0.05 ), while T1/2 of them notably increased when compared with normal rats treated with Fuzi. The parameters were the same trend in model rats treated with Fuzi-Banxia comparing with accordingly normal group.These results indicated that Banxia could enhance the absorption of Aconitum alkaloids and promote their elimination in normal rats, but had no effect on the absorption of Aconitum alkaloids in model rats. The results also indicated that the absorption of Aconitum alkaloids reduced and their