Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.16.1.13
M. Jann, L. Jaime
A symposium was held from April 26-28, 1998 in Trinidad and Tobago that brought together a variety of scientists from Europe and North America to discuss the latest findings regarding psychopharmacology and ethnicity. Many of the meeting's attendees were physicians and scientists from the Caribbean region. Although this meeting was held almost two years ago, many of its findings remain relevant in the evaluation of drug response in different ethnic populations. There were eleven different presentations and discussion groups. These presentations focused on three basic and clinical areas: pharmacogenetics and drug metabolism, the effects of antipsychotics and the effects of antidepressants. There were two presentations that emphasized a genetic basis in the metabolism of psychotropic drugs with two specific cytochrome P-450 (CYP) isozymes, 2D6 and 2C19. Other topics presented were the treatment of refractory bipolar disorders, substance abuse and methodological issues in the studies of ethnicity and psychotropic drugs.
{"title":"AN INTERNATIONAL SYMPOSIUM ON PSYCHOPHARMACOLOGY AND ETHNICITY","authors":"M. Jann, L. Jaime","doi":"10.1515/DMDI.2000.16.1.13","DOIUrl":"https://doi.org/10.1515/DMDI.2000.16.1.13","url":null,"abstract":"A symposium was held from April 26-28, 1998 in Trinidad and Tobago that brought together a variety of scientists from Europe and North America to discuss the latest findings regarding psychopharmacology and ethnicity. Many of the meeting's attendees were physicians and scientists from the Caribbean region. Although this meeting was held almost two years ago, many of its findings remain relevant in the evaluation of drug response in different ethnic populations. There were eleven different presentations and discussion groups. These presentations focused on three basic and clinical areas: pharmacogenetics and drug metabolism, the effects of antipsychotics and the effects of antidepressants. There were two presentations that emphasized a genetic basis in the metabolism of psychotropic drugs with two specific cytochrome P-450 (CYP) isozymes, 2D6 and 2C19. Other topics presented were the treatment of refractory bipolar disorders, substance abuse and methodological issues in the studies of ethnicity and psychotropic drugs.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"16 1","pages":"13 - 14"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.16.1.13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67181952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.16.4.281
G. Byrd, W. Caldwell, B. Bhatti, A. Ravard, P. Crooks
[Methyl-d3]-N-1-beta-D-glucopyranosyl-(+/-)-nicotinium inner salt ((+/-)-[methyl-d3]nicotine N-1-glucuronide) was synthesized from (+/-)-[methyl-d3]nicotine via reaction with methyl-2,3,4-tri-O-acetyl-1-bromodeoxy-alpha-D-glucopyranouronate, followed by deprotection with 1 M aqueous NaOH and purification by preparative TLC. Nicotine N-glucuronide was identified and determined directly in smokers' urine. A solid phase extraction method was used to partially isolate the material from urine. Subsequent determination was by thermospray-LC/MS using the synthetic d3-labeled nicotine N-glucuronide as internal standard. The identified urinary component had the same retention time as a synthetic standard and gave the same mass spectrum. The thermospray mass spectrum was characterized from the protonated molecular ion (m/z 339) and the protonated aglycone ion (m/z 163). Quantitative results from this direct method were compared with those from an indirect method, which calculated the nicotine glucuronide in the biological sample from the amount of nicotine released following treatment of the sample with the deconjugating enzyme, beta-glucuronidase. On average, the concentration of nicotine N-glucuronide determined by the direct method was 34% greater than that determined by the indirect method. Concentrations of nicotine N-glucuronide in urine ranged from 2.2 to 7.6 nmol/ml with a limit of detection of 1.3 nmol/ml.
以(+/-)-[甲基-d3]烟碱为原料，与甲基-2,3,4-三- o -乙酰-1-溴脱氧- -d -葡萄糖醛酸盐反应，合成[甲基-d3]- n -1- β -d -葡萄糖醛酸盐((+/-)-[甲基-d3]烟碱n -1-葡萄糖醛酸盐)，用1 M NaOH水溶液去保护，制备层析纯化。在吸烟者尿液中直接鉴定并测定尼古丁n -葡糖苷。采用固相萃取法从尿液中部分分离出该物质。采用热喷雾-液相色谱/质谱法测定，以合成的d3标记尼古丁n -葡糖苷为内标。所鉴定的尿液成分与合成标准品具有相同的保留时间，并具有相同的质谱。热喷雾质谱由质子化分子离子(m/z 339)和质子化苷元离子(m/z 163)表征。将直接法的定量结果与间接法的定量结果进行了比较，间接法是通过解结酶-葡糖苷酶处理后的尼古丁释放量来计算生物样品中的尼古丁葡萄糖醛酸盐。直接法测定的烟碱n -葡糖苷浓度平均比间接法测定的高34%。尿中尼古丁n -葡萄糖醛酸盐浓度为2.2 ~ 7.6 nmol/ml，检出限为1.3 nmol/ml。
{"title":"Determination of Nicotine N-1-Glucuronide, a Quaternary N-Glucuronide Conjugate, in Human Biological Samples","authors":"G. Byrd, W. Caldwell, B. Bhatti, A. Ravard, P. Crooks","doi":"10.1515/DMDI.2000.16.4.281","DOIUrl":"https://doi.org/10.1515/DMDI.2000.16.4.281","url":null,"abstract":"[Methyl-d3]-N-1-beta-D-glucopyranosyl-(+/-)-nicotinium inner salt ((+/-)-[methyl-d3]nicotine N-1-glucuronide) was synthesized from (+/-)-[methyl-d3]nicotine via reaction with methyl-2,3,4-tri-O-acetyl-1-bromodeoxy-alpha-D-glucopyranouronate, followed by deprotection with 1 M aqueous NaOH and purification by preparative TLC. Nicotine N-glucuronide was identified and determined directly in smokers' urine. A solid phase extraction method was used to partially isolate the material from urine. Subsequent determination was by thermospray-LC/MS using the synthetic d3-labeled nicotine N-glucuronide as internal standard. The identified urinary component had the same retention time as a synthetic standard and gave the same mass spectrum. The thermospray mass spectrum was characterized from the protonated molecular ion (m/z 339) and the protonated aglycone ion (m/z 163). Quantitative results from this direct method were compared with those from an indirect method, which calculated the nicotine glucuronide in the biological sample from the amount of nicotine released following treatment of the sample with the deconjugating enzyme, beta-glucuronidase. On average, the concentration of nicotine N-glucuronide determined by the direct method was 34% greater than that determined by the indirect method. Concentrations of nicotine N-glucuronide in urine ranged from 2.2 to 7.6 nmol/ml with a limit of detection of 1.3 nmol/ml.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"16 1","pages":"281 - 298"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.16.4.281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67182664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.23
T.J. Smith, Cs Yang
The frequent consumption of cruciferous vegetables and garlic is associated with several health benefits. These foods contain organosulfur compounds that are known to affect the biotransformation of xenobiotics, and therefore can influence the toxicity and carcinogenicity of environmental chemicals. In this article, we review the effects of isothiocyanates and diallyl sulfide on xenobiotic metabolism and the enzymes involved in the process. Isothiocyanates and diallyl sulfide can modulate the levels of phase I and phase II drug-metabolizing enzymes by affecting the transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes, or the enzyme activity. These compounds are not general enzyme inhibitors or inducers. They elicit selectivity in their mode of action. Elucidating the mechanisms involved in the alteration of drug-metabolizing enzymes by isothiocyanates and diallyl sulfide will increase our understanding of their possible effects on the biotransformation of drugs as well as the potential beneficial or detrimental effects of these organosulfur compounds.
{"title":"Effect of Organosulfur Compounds from Garlic and Cruciferous Vegetables on Drug Metabolism Enzymes","authors":"T.J. Smith, Cs Yang","doi":"10.1515/DMDI.2000.17.1-4.23","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.23","url":null,"abstract":"The frequent consumption of cruciferous vegetables and garlic is associated with several health benefits. These foods contain organosulfur compounds that are known to affect the biotransformation of xenobiotics, and therefore can influence the toxicity and carcinogenicity of environmental chemicals. In this article, we review the effects of isothiocyanates and diallyl sulfide on xenobiotic metabolism and the enzymes involved in the process. Isothiocyanates and diallyl sulfide can modulate the levels of phase I and phase II drug-metabolizing enzymes by affecting the transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes, or the enzyme activity. These compounds are not general enzyme inhibitors or inducers. They elicit selectivity in their mode of action. Elucidating the mechanisms involved in the alteration of drug-metabolizing enzymes by isothiocyanates and diallyl sulfide will increase our understanding of their possible effects on the biotransformation of drugs as well as the potential beneficial or detrimental effects of these organosulfur compounds.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"23 - 50"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67183124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.3
T. Kensler, T. Curphey, Y. Maxiutenko,, B. Roebuck
One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Alliaceous and cruciferous plants are rich in organosulfur compounds with inducer activity. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, dithiins and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of aflatoxin B1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the Antioxidant Response Element, leading to transcriptional activation of a score of genes involved in carcinogen detoxification and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to oltipraz and the impact of this genotype on the chemopreventive efficacy of dithiolethiones is currently under investigation. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, P.R. China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB1, aflatoxin M1, when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population. Food-based approaches to chem
{"title":"Chemoprotection by Organosulfur Inducers of Phase 2 Enzymes: Dithiolethiones and Dithiins","authors":"T. Kensler, T. Curphey, Y. Maxiutenko,, B. Roebuck","doi":"10.1515/DMDI.2000.17.1-4.3","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.3","url":null,"abstract":"One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Alliaceous and cruciferous plants are rich in organosulfur compounds with inducer activity. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, dithiins and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of aflatoxin B1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the Antioxidant Response Element, leading to transcriptional activation of a score of genes involved in carcinogen detoxification and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to oltipraz and the impact of this genotype on the chemopreventive efficacy of dithiolethiones is currently under investigation. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, P.R. China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB1, aflatoxin M1, when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population. Food-based approaches to chem","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"22 - 3"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67182818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.189
S. Agarwal, A. Rao
Chronic diseases such as cancer and cardiovascular diseases are the major causes of deaths in North America. Dietary intake of fruits and vegetables has been suggested to have protective effects against such chronic diseases. Carotenoids are important plant pigments which are thought to contribute towards the beneficial effects of fruit and vegetable consumption. This review focuses on the role of carotenoids and particularly lycopene in chronic diseases.
{"title":"Carotenoids and Chronic Diseases","authors":"S. Agarwal, A. Rao","doi":"10.1515/DMDI.2000.17.1-4.189","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.189","url":null,"abstract":"Chronic diseases such as cancer and cardiovascular diseases are the major causes of deaths in North America. Dietary intake of fruits and vegetables has been suggested to have protective effects against such chronic diseases. Carotenoids are important plant pigments which are thought to contribute towards the beneficial effects of fruit and vegetable consumption. This review focuses on the role of carotenoids and particularly lycopene in chronic diseases.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"189 - 210"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67182287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.16.4.307
D. Lewis
Cytochrome P450 (CYP) enzymes represent the major catalysts for the Phase 1 metabolism of drugs and other xenobiotics in Mammalia, including Homo sapiens. There is considerable current interest in evaluating and, consequently, predicting the metabolic fate of new chemical entities (NCEs) via modelling molecular interactions with P450 constructs, such that sites of metabolism, particular CYP involvement and binding affinities, can be estimated. This paper focuses on the principles for homology modelling of typical enzyme-substrate interactions within the putative active sites of major P450s associated with drug metabolism in man. It also represents an update on previously published work in this journal /1/.
{"title":"Modelling Human Cytochromes P450 for Evaluating Drug Metabolism: An Update","authors":"D. Lewis","doi":"10.1515/DMDI.2000.16.4.307","DOIUrl":"https://doi.org/10.1515/DMDI.2000.16.4.307","url":null,"abstract":"Cytochrome P450 (CYP) enzymes represent the major catalysts for the Phase 1 metabolism of drugs and other xenobiotics in Mammalia, including Homo sapiens. There is considerable current interest in evaluating and, consequently, predicting the metabolic fate of new chemical entities (NCEs) via modelling molecular interactions with P450 constructs, such that sites of metabolism, particular CYP involvement and binding affinities, can be estimated. This paper focuses on the principles for homology modelling of typical enzyme-substrate interactions within the putative active sites of major P450s associated with drug metabolism in man. It also represents an update on previously published work in this journal /1/.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"16 1","pages":"307 - 324"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.16.4.307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67182395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.51
A. le Bon, M. Siess
Allium vegetables and their associated organosulfur constituents are extensively studied for their chemopreventive potential against cancer. This article overviews their anticarcinogenic and antigenotoxic properties. Epidemiological studies (mostly case-control studies) provide strong evidence that Allium vegetable consumption reduces the incidence of gastric and colon cancer while the association between Allium vegetable consumption and other cancers is less convincing. Furthermore, many experimental studies have demonstrated that organosulfur compounds and Allium extracts have inhibitory effects on carcinogenesis in animals. These inhibitory effects are supported by many diverse mechanisms, including inhibition of carcinogen formation, modulation of carcinogen metabolism, inhibition of mutagenesis and genotoxicity, inhibition of cell proliferation and increase of apoptosis, inhibition of angiogenesis, and immune system enhancement. Before such constituents or extracts can be used in chemopreventive trials, it is important to verify their lack of toxicity and to investigate further their precise mechanisms of action throughout the whole process of carcinogenesis.
{"title":"Organosulfur Compounds from Allium and the Chemoprevention of Cancer","authors":"A. le Bon, M. Siess","doi":"10.1515/DMDI.2000.17.1-4.51","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.51","url":null,"abstract":"Allium vegetables and their associated organosulfur constituents are extensively studied for their chemopreventive potential against cancer. This article overviews their anticarcinogenic and antigenotoxic properties. Epidemiological studies (mostly case-control studies) provide strong evidence that Allium vegetable consumption reduces the incidence of gastric and colon cancer while the association between Allium vegetable consumption and other cancers is less convincing. Furthermore, many experimental studies have demonstrated that organosulfur compounds and Allium extracts have inhibitory effects on carcinogenesis in animals. These inhibitory effects are supported by many diverse mechanisms, including inhibition of carcinogen formation, modulation of carcinogen metabolism, inhibition of mutagenesis and genotoxicity, inhibition of cell proliferation and increase of apoptosis, inhibition of angiogenesis, and immune system enhancement. Before such constituents or extracts can be used in chemopreventive trials, it is important to verify their lack of toxicity and to investigate further their precise mechanisms of action throughout the whole process of carcinogenesis.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"51 - 80"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.51","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67183200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.351
Hu Zhang, C. W. Wong, P. Coville, S. Wanwimolruk
The effect of the grapefruit flavonoid naringin, an inhibitor of CYP3A4, on the pharmacokinetics of quinine in rats after oral or intravenous (i.v.) dosing of quinine was investigated. Female Wistar rats (wt 190-220 g) were used in two separate studies, i.e. oral and i.v. administration of quinine. The animals were divided into two groups, one served as control and the other group was pretreated with 25 mg/kg naringin once a day for 7 consecutive days before the pharmacokinetic study. On the study day, quinine (25 mg/kg) was administered to the rats by either the oral or i.v. route. Blood samples were collected at different times, up to 6 h after quinine administration. Plasma quinine concentration was assayed by HPLC. Pretreatment with naringin did not cause any significant change in the pharmacokinetics of quinine after the i.v. dose. However pretreatment with naringin led to a 208% increase in peak plasma concentration (Cmax), a 93% increase in time to reach Cmax (tmax), and a 152% increase in the area under the plasma concentration-time curve (AUC) of quinine after oral administration. Consequently, the oral bioavailability of quinine was significantly increased (p < 0.05) from 17% (control) to 42% after pretreatment with naringin. There was no significant difference in the elimination half-life (t(1/2)beta) of quinine between the two groups. These results suggest that pretreatment with the grapefruit flavonoid naringin is associated with increased oral bioavailability of quinine in rats.
{"title":"Effect of the Grapefruit Flavonoid Naringin on Pharmacokinetics of Quinine in Rats","authors":"Hu Zhang, C. W. Wong, P. Coville, S. Wanwimolruk","doi":"10.1515/DMDI.2000.17.1-4.351","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.351","url":null,"abstract":"The effect of the grapefruit flavonoid naringin, an inhibitor of CYP3A4, on the pharmacokinetics of quinine in rats after oral or intravenous (i.v.) dosing of quinine was investigated. Female Wistar rats (wt 190-220 g) were used in two separate studies, i.e. oral and i.v. administration of quinine. The animals were divided into two groups, one served as control and the other group was pretreated with 25 mg/kg naringin once a day for 7 consecutive days before the pharmacokinetic study. On the study day, quinine (25 mg/kg) was administered to the rats by either the oral or i.v. route. Blood samples were collected at different times, up to 6 h after quinine administration. Plasma quinine concentration was assayed by HPLC. Pretreatment with naringin did not cause any significant change in the pharmacokinetics of quinine after the i.v. dose. However pretreatment with naringin led to a 208% increase in peak plasma concentration (Cmax), a 93% increase in time to reach Cmax (tmax), and a 152% increase in the area under the plasma concentration-time curve (AUC) of quinine after oral administration. Consequently, the oral bioavailability of quinine was significantly increased (p < 0.05) from 17% (control) to 42% after pretreatment with naringin. There was no significant difference in the elimination half-life (t(1/2)beta) of quinine between the two groups. These results suggest that pretreatment with the grapefruit flavonoid naringin is associated with increased oral bioavailability of quinine in rats.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"351 - 364"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67183644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.211
Rao Av, Gurfinkel Dm
Triterpenoid and steroidal glycosides, referred to collectively as saponins, are bioactive compounds present naturally in many plants. They have considerable potential as pharmaceutical and/or nutraceutical agents in natural or synthetic form. Saponins, from a variety of sources, have been shown to have hypocholesterolemic, anti-coagulant, anticarcinogenic, hepatoprotective, hypoglycemic, immunomodulatory, neuroprotective, anti-inflammatory and anti-oxidant activity. This paper reviews saponin research of the last decade, focussing on developments in understanding their mechanism of action and structure-activity relationships. Virtually all of this work has used animal and in vitro models. To date there are very few human data.
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Pub Date : 2000-01-01DOI: 10.1515/DMDI.2000.17.1-4.109
M. Cuendet, J. Pezzuto
The involvement of prostaglandins (PGs) and other eicosanoids in the development of human cancer has been known for over two decades. Importantly, an increase in PG synthesis may influence tumor growth in human beings and experimental animals, and numerous studies have illustrated the effect of PG synthesis on carcinogen metabolism, tumor cell proliferation and metastatic potential. PGs produced by cyclooxygenases (COXs) are represented by a large series of compounds that mainly enhance cancer development and progression, acting as carcinogens or tumor promoters, with profound effects on carcinogenesis. Further investigations suggest that arachidonic acid (AA) metabolites derived from lipoxygenase (LOX) pathways play an important role in growth-related signal transduction, implying that intervention through these pathways should be useful for arresting cancer progression. We discuss here the implications of COX and LOX in colon, pancreatic, breast, prostate, lung, skin, urinary bladder and liver cancers. Select inhibitors of COX and LOX are described, including nonsteroidal antiinflammatory drugs (NSAIDs), selective COX-2 inhibitors, curcumin, tea, silymarin and resveratrol, as well as a method useful for evaluating inhibitors of COX. Although a substantial amount of additional work is required to yield a better understanding of the role of COX and LOX in cancer chemoprevention, it is clear that beneficial therapeutic effects can be realized through drug-mediated modulation of these metabolic pathways.
{"title":"The Role of Cyclooxygenase and Lipoxygenase in Cancer Chemoprevention","authors":"M. Cuendet, J. Pezzuto","doi":"10.1515/DMDI.2000.17.1-4.109","DOIUrl":"https://doi.org/10.1515/DMDI.2000.17.1-4.109","url":null,"abstract":"The involvement of prostaglandins (PGs) and other eicosanoids in the development of human cancer has been known for over two decades. Importantly, an increase in PG synthesis may influence tumor growth in human beings and experimental animals, and numerous studies have illustrated the effect of PG synthesis on carcinogen metabolism, tumor cell proliferation and metastatic potential. PGs produced by cyclooxygenases (COXs) are represented by a large series of compounds that mainly enhance cancer development and progression, acting as carcinogens or tumor promoters, with profound effects on carcinogenesis. Further investigations suggest that arachidonic acid (AA) metabolites derived from lipoxygenase (LOX) pathways play an important role in growth-related signal transduction, implying that intervention through these pathways should be useful for arresting cancer progression. We discuss here the implications of COX and LOX in colon, pancreatic, breast, prostate, lung, skin, urinary bladder and liver cancers. Select inhibitors of COX and LOX are described, including nonsteroidal antiinflammatory drugs (NSAIDs), selective COX-2 inhibitors, curcumin, tea, silymarin and resveratrol, as well as a method useful for evaluating inhibitors of COX. Although a substantial amount of additional work is required to yield a better understanding of the role of COX and LOX in cancer chemoprevention, it is clear that beneficial therapeutic effects can be realized through drug-mediated modulation of these metabolic pathways.","PeriodicalId":77889,"journal":{"name":"Reviews on drug metabolism and drug interactions","volume":"17 1","pages":"109 - 158"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2000.17.1-4.109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67182636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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