左旋一叶碱的代谢转化

目的研究一叶碱［securinine,(-)SE］在大鼠体内外的代谢转化。方法采用大鼠肝微粒体体外温孵法对(-)SE的代谢转化进行了研究,优化了代谢体系,建立了反相HPLC法同时分离检测(-)SE及其体外代谢产物的分析方法。用液液萃取,制备TLC及半制备HPLC分离纯化了4个代谢产物并进行了光谱鉴定。在此基础上,建立了生物体液中(-)SE及其代谢物的反相HPLC分析方法,并用该法检测了ip给药后大鼠的胆汁、尿样及其经β-葡糖醛酸苷酶水解后的样品。结果代谢物分别鉴定为6-位羟基,6-位羰基及5-位α及β羟基取代的(-)SE,还证实了体内6-位羟基代谢物进一步形成了二相结合型产物。结论基本阐明(-)SE在大鼠体内外代谢转化的途径。     

左旋一叶萩碱的代谢转化

目的　研究一叶碱 [securinine ,( - )SE]在大鼠体内外的代谢转化。方法　采用大鼠肝微粒体体外温孵法对 ( - )SE的代谢转化进行了研究 ,优化了代谢体系 ,建立了反相HPLC法同时分离检测 ( - )SE及其体外代谢产物的分析方法。用液液萃取 ,制备TLC及半制备HPLC分离纯化了 4个代谢产物并进行了光谱鉴定。在此基础上 ,建立了生物体液中 ( - )SE及其代谢物的反相HPLC分析方法 ,并用该法检测了ip给药后大鼠的胆汁、尿样及其经 β 葡糖醛酸苷酶水解后的样品。结果　代谢物分别鉴定为 6 位羟基 ,6 位羰基及 5 位α及 β羟基取代的 ( - )SE ,还证实了体内 6 位羟基代谢物进一步形成了二相结合型产物。结论　基本阐明 ( - )SE在大鼠体内外代谢转化的途径     

左旋黄皮酰胺在大鼠肝微粒体中的代谢转化研究

用大鼠肝微粒体体外温孵法进行了左旋黄皮酰胺[(-)-clausenamide]代谢转化研究,优化了温孵体系,建立了反相HPLC-DAD同时分离检测左旋黄皮酰胺及其体外代谢产物的分析方法。用硅胶低压柱色谱、制备TLC及制备HPLC分离纯化了两个代谢产物并进行了光谱鉴定。结果表明,两个代谢物分别确定为6-和5-位羟基取代的黄皮酰胺。     

五味子醇甲的代谢转化

采用动物肝微粒体体外代谢法对五味子醇甲的代谢转化进行了研究。从体外代谢产物中鉴定其主要的三个代谢物为:7,8-顺二羟基五味子酸甲;7,7-顺二羟基-2-去甲基五味子醇甲及7,8-顺二羟基-3-去甲基五味子醇甲。在此基础上,建立了生物体液中五味子醇甲及其代谢物的反相HPLC分析方法,并用此法检测了服药后大鼠的胆汁及尿样,比较了体外代谢与体内代谢的异同。     

海南粗榧新碱衍生物HH07A经大鼠肝微粒体的代谢转化研究

用大鼠肝微粒体体外代谢法对HH07A进行了代谢转化研究。用HPLC结合二极管阵列检测器对体外代谢体系进行了分析,判断在体外代谢体系中HH07A有二个代谢产物,并用减压柱色谱、薄层色谱及高效液相色谱法分离制备了其中一个代谢物的纯品,经核磁共振、质谱、红外、紫外光谱确定了结构。     

普罗帕酮在中国健康受试者体内的羟基化代谢产物研究

目的:阐明普罗帕酮羟基化代谢过程的种属及种族差异。方法:选择10 名中国健康受试者单剂量po300 mg 盐酸普罗帕酮片,收集0 ～12 h 的尿样,经液 液萃取后,采用LC/ MSⁿ 技术,对羟基化代谢产物进行选择性离子监测(m/z 358) 和多级全扫描质谱分析。结果:在服药后的尿样中检测到两种羟基化代谢产物,根据质谱数据,推测这两种代谢产物分别为4′-羟基普罗帕酮和5-羟基普罗帕酮。采用微生物转化法结合半制备HPLC制备并分离了4′-羟基普罗帕酮的对照品,通过NMR 证实了其结构。结论:在10 名受试者服药后的尿样中均能检测到代谢物4′ 羟基普罗帕酮和5 羟基普罗帕酮,与文献报道的白人受试者代谢结果相比,中国受试者有较宽的羟基化代谢谱。     

三尖杉酯碱类似物的半合成

本文报道了由三尖杉碱Ⅰ合成了三个三尖杉酯碱的类似物Ⅱ,Ⅲ,Ⅳ。化合物Ⅱ由三尖杉碱与羟基保护的2-羟基2-甲基丁酸的羟基,用三氯乙氧基碳酰基保护后制成酰氯,后者与Ⅰ缩合,用锌-乙酸除去保护基即得Ⅱ。3-羟基-3-甲氧羰基-6-甲基庚酸甲酯用二氯化亚砜     

人尿中苯丙哌林羟基化代谢产物的研究

目的　研究苯丙哌林在人体内的羟基化代谢过程。方法　选择10名健康男性受试者单剂量口服60 mg苯丙哌林,收集0～24 h尿样,经固相萃取后用LC/MSⁿ法检测羟基化代谢产物。利用微生物转化法和半制备HPLC获得其中两种代谢产物的对照品,并经NMR鉴定结构。根据质谱断裂规律进一步推测结合型代谢物的结构。结果 在人尿中发现苯丙哌林的5种羟基化代谢产物和它们与内源性葡糖醛酸和硫酸的结合物,与代谢物对照品的液相色谱和质谱信息比较,确证了其中两种代谢产物的结构分别为4″-羟基苯丙哌林和4″-羟基苯丙哌林。结论　苯丙哌林的羟基化代谢优先发生在芳环烷氧基对位,5种羟基化代谢产物在尿中主要以葡糖苷酸或硫酸酯结合物形式存在。     

高三尖杉酯碱酰胺的结构测定

三尖杉树皮粗提取物中的一个新生物碱—高三尖杉酯碱酰胺(homoharringtonamide)的结构,经质谱—质谱分析,初步建议为16。类似的酰胺类生物碱,例如三尖杉碱酰胺(cephalotaxamide,6)、11-羟基三尖杉碱酰胺(11-hydroxycephalotaxamide,9)、三尖杉酯碱酰胺(harfingtonamide,14)或异三尖杉酯碱酰胺(isoharringtonamide,15)也可能存在,后三者(9,14,15)尚未见报道。     

高三尖杉酯碱乳膏体外透皮吸收作用研究

（1. ［摘要］目的探讨高三尖杉酯碱乳膏体外透皮吸收作用。方法采用小鼠体外皮肤作为渗透屏障,研究不同浓度氮酮对高三尖杉酯碱促渗作用的影响。结果氮酮可显著提高高三尖杉酯碱对皮肤的渗透作用,含2%和5%氮酮的乳膏渗透速率比空白乳膏分别增加了56.88%和89.51%。结论高三尖杉酯碱乳膏具有良好的皮肤渗透性,5%氮酮对其促渗效果最好。     

Determination of the human cytochrome P450s involved in the metabolism of 2n-propylquinoline

1 2n-Propylquinoline (2nPQ) is a newly developed drug for visceral antileishmaniasis and its activity has been previously evaluated in mice following oral administration. The study was carried out to investigate the kinetic formation of 2nPQ metabolites and to characterize the human liver CYP forms involved in its oxidative metabolism. 2. The inhibition of 2nPQ metabolite formation by specific substrates or inhibitors of CYP forms and correlation studies were performed in human liver microsomes. 2nPQ biotransformation was then studied in human lymphoblasts expressing specific CYPs and microsomal epoxide hydrolase. 3. Three major metabolites were produced by human liver microsomes and their structures were identified by ESI-LC/MS: dihydroxy-2n-propylquinoline, 3'-hydroxy-2n-propylquinoline and 1'-hydroxy-2n-propylquinoline. An intermediary metabolite, epoxy-2n-propylquinoline, formed by CYP was also biotransformed by microsomal epoxide hydrolase into dihydroxy-2n-propylquinoline. 4. 2nPQ oxidation follows Michaelis-Menten kinetics. In human liver microsomes, its metabolism was extremely inhibited by pilocarpine, coumarin and diethyldithiocarbamate. From a panel of 12 human liver microsome samples, the rate of 2nPQ oxidation was highly correlated with the activities of CYP2A6 and CYP2E1. Human lymphoblasts expressing specific CYPs showed the involvement of CYP2A6, CYP2E1 and CYP2C19. 5. The results indicate that 2nPQ metabolites are 3'- and 1'-hydroxylated by human liver microsomes and an epoxy-2n-propylquinoline is biotransformed into a dihydroxy-2n-propylquinoline by microsomal epoxide hydrolase.     

Characterization of metabolites of xylazine produced in vivo and in vitro by LC/MS/MS and by GC/MS.

The metabolic fate of xylazine, 2-(2,6-dimethylphenylamino)-5,6-dihydro-4H-1,3-thiazine, in horses is described. The major metabolites identified in the hydrolyzed horse urine were 2-(4'-hydroxy-2',6'-dimethylphenylamino)-5,6-dihydro-4H-1,3-thiazi ne, 2-(3'-hydroxy-2',6'-dimethylphenylamino)-5,6-dihydro-4H-1,3-thiazi ne, N-(2,6-dimethylphenyl)thiourea, and 2-(2',6'-dimethylphenylamino)-4-oxo-5,6-dihydro-1,3-thiazine. These metabolites were also produced by incubating xylazine with rat liver microsomes. The major metabolite produced in vitro by rat liver preparations was found to be the ring opened N-(2,6-dimethylphenyl)thiourea. The identities of these metabolites were confirmed by spectroscopic comparisons with synthetic standards. Phenolic metabolic standards were synthesized efficiently by the use of Fenton's reagent. This reagent was used to monohydroxylate multiply substituted aromatic ring systems. LC/MS/MS, with an atmospheric pressure chemical ionization source, was found to be particularly useful in confirming the presence of phenolic metabolites in hydrolyzed equine urine and microsomal extracts. These phenolic metabolites could not be analyzed by GC/MS even after derivatization with silylating agents. The advantage of LC/MS/MS was that no or little sample preparation of urine or microsomal extract was necessary prior to the analysis. A mechanism is also proposed for the formation of the major metabolite, N-(2,6-dimethylphenyl)thiourea, from xylazine.     

Sex difference in the stereoselective metabolism of a new dihydropyridine calcium channel blocker, in rat studies in vivo and in vitro

1. After oral dosing with a new racemic dihydropyridine calcium channel blocker (I), plasma levels of (+/-)-I, the 3-desisopropyl metabolite (M-2), the pyridine metabolite (M-3) and the 5-desmethyl metabolite (M-10) in female rats were higher than in males, and plasma levels of (+)-I were higher than those of the (-)-enantiomer in both sexes. 2. Plasma levels of M-2 after oral dosing with (-)-I were much higher than those after dosing with (+)-I, in both male and female rats. 3. Stereoselective metabolism of I by rat liver microsomes was shown in the formation of the 3-(2'-hydroxy-1'-methylethyl) ester metabolite (M-1), and metabolites M-2 and M-10. 4. Marked sex differences were seen in the formation of M-1 and M-3 in adult rats (7 weeks of age), but not in immature rats (3 weeks of age). 5. In liver microsomes of rats pretreated with phenobarbital, the formation of M-1 was decreased in adult male rats, and formation of M-2 and M-3 was increased in adult rats of both sexes.     

The disposition and metabolism of flurbiprofen in several species including man.

Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.     

An unusual metabolite of testosterone. 17 beta-Hydroxy-4,6-androstadiene-3-one

A testosterone metabolite, 17 beta-hydroxy-4,6-androstadiene-3-one, possessing an absorbance maximum at 284 nm, was formed during incubation of testosterone with liver microsomes from dexamethasone-treated rats. The metabolite was identified by HPLC, UV spectroscopy, and thermospray liquid chromatography/mass spectrometry. The formation of this metabolite by rat liver microsomes required NADPH and oxygen and was inhibited markedly by SKF 525-A, 2,4-dichloro-6-phenylphenoxyethylamine, or CO/O2 (8:2, v/v), but not by cyanide, an inhibitor for stearyl-CoA desaturase. Pretreatment of rats with phenobarbital, pregnenolone 16 alpha-carbonitrile, and dexamethasone enhanced the formation of this metabolite in parallel with the increase in formation of 6 beta-hydroxytestosterone (r2 = 0.99). Although 16-methylprogesterone, a known 6 beta-hydroxylase inhibitor, competitively inhibited the formation of the metabolite and 6 beta-hydroxytestosterone by liver microsomes from dexamethasone-treated rats, the metabolite was not formed from either 6 beta-hydroxytestosterone or 7-hydroxytestosterone during incubation with liver microsomes. These findings are consistent with the view that cytochrome P-450 isozymes that catalyze 6 beta-hydroxylation of steroids in rat liver microsomes also catalyze the dehydrogenation of testosterone to form a double bond between the C-6 and C-7 positions.     

Involvement of CYP2A6 in the formation of a novel metabolite, 3-hydroxypilocarpine, from pilocarpine in human liver microsomes.

Pilocarpine is a cholinergic agonist that is metabolized to pilocarpic acid by serum esterase. In this study, we discovered a novel metabolite in human urine after the oral administration of pilocarpine hydrochloride, and we investigated the metabolic enzyme responsible for the metabolite formation. The structure of the metabolite was identified as 3-hydroxypilocarpine by liquid chromatography-tandem mass spectrometry and NMR analyses and by comparing to the authentic metabolite. To clarify the human cytochrome P450 (P450) responsible for the metabolite formation, in vitro experiments using P450 isoform-selective inhibitors, cDNA-expressed human P450s (Supersomes; CYP1A2, -2A6, -2B6, -2C9, -2C19, -2D6, -2E1, and -3A4), and liver microsomes from different donors were conducted. The formation of 3-hydroxypilocarpine in human liver microsomes was strongly inhibited (>90%) by 200 microM coumarin. Other selective inhibitors of CYP1A2 (furafylline and alpha-naphthoflavone), CYP2C9 (sulfaphenazole), CYP2C19 [(S)-mephenytoin], CYP2E1 (4-methylpyrazole), CYP2D6 (quinidine), and CYP3A4 (troleandomycin) had a weak inhibitory effect (<20%) on the formation. The highest formation activity was expressed by recombinant CYP2A6. The K(m) value for recombinant CYP2A6 was 3.1 microM, and this value is comparable with that of human liver microsomes (1.5 microM). The pilocarpine 3-hydroxylation activity was correlated with coumarin 7-hydroxylation activity in 16 human liver microsomes (r = 0.98). These data indicated that CYP2A6 is the main enzyme responsible for the 3-hydroxylation of pilocarpine. In conclusion, we identified a novel metabolite of pilocarpine, 3-hydroxypilocarpine, and we clarified the involvement of CYP2A6 in the formation of this molecule in human liver microsomes.     

Detection of a novel reactive metabolite of diclofenac: evidence for CYP2C9-mediated bioactivation via arene oxides.

A new glutathione adduct (M4) was tentatively identified, likely as 2'-hydroxy-3'-(glutathione-S-yl)-monoclofenac, using liquid chromatography-tandem mass spectrometry analysis of incubations of diclofenac with human liver microsomes. The same conjugate was not detected in incubations with either rat or monkey liver microsomes. Formation of M4 was mediated specifically by CYP2C9 in human liver microsomes, as evidenced by the following observations: 1) cDNA-expressed CYP2C9-catalyzing formation of M4; 2) inhibition of M4 formation by sulfaphenazole, a CYP2C9-selective inhibitor; and 3) strong correlation between the production of M4 and CYP2C9-mediated tolbutamide 4-hydroxylase activities in a panel of human liver microsome samples. Formation of M4 suggests the existence of a new reactive intermediate as diclofenac-2',3'-oxide. A tentative pathway states that diclofenac is oxidized to diclofenac-2',3'-oxide that reacts with glutathione (GSH) to form a thioether conjugate at the C-3' position, followed by a concomitant loss of chlorine to give rise to M4. Furthermore, a likely mechanism leading to the formation of diclofenac oxides is rationalized: CYP2C9-catalyzed oxidation at the C-3' position of the dichlorophenyl ring to form a cationic sigma-complex that subsequently results in diclofenac-3',4'-oxide and diclofenac-2',3'-oxide; the former oxide is converted to 4'-hydroxy-diclofenac as a major metabolite and can be trapped by GSH to produce 4'-hydroxy-3'-glutathione-S-yl diclofenac (M2), whereas the latter oxide forms 3'-hydroxy-diclofenac and can be trapped by GSH to produce M4. This mechanism is consistent with the structural modeling of the CYP2C9-diclofenac complex, which reveals that both the C-3' and C-4' of the dichlorophenyl ring are proximate to the heme group.     

Metabolism of [6]-shogaol in mice and in cancer cells

Ginger has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from [6]-shogaol-treated mice. Their structures were elucidated as 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 5-methoxy-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M7), 3',4'-dihydroxyphenyl-decan-3-one (M8), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M10), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), and 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M12) on the basis of detailed analysis of their (1)H, (13)C, and two-dimensional NMR data. The rest of the metabolites were identified as 5-cysteinyl-M6 (M1), 5-cysteinyl-[6]-shogaol (M2), 5-cysteinylglycinyl-M6 (M3), 5-N-acetylcysteinyl-M6 (M4), 5-N-acetylcysteinyl-[6]-shogaol (M5), and 5-glutathiol-[6]-shogaol (M13) by analysis of the MS(n) (n = 1-3) spectra and comparison to authentic standards. Among the metabolites, M1 through M5, M10, M12, and M13 were identified as the thiol conjugates of [6]-shogaol and its metabolite M6. M9 and M11 were identified as the major metabolites in four different cancer cell lines (HCT-116, HT-29, H-1299, and CL-13), and M13 was detected as a major metabolite in HCT-116 human colon cancer cells. We further showed that M9 and M11 are bioactive compounds that can inhibit cancer cell growth and induce apoptosis in human cancer cells. Our results suggest that 1) [6]-shogaol is extensively metabolized in these two models, 2) its metabolites are bioactive compounds, and 3) the mercapturic acid pathway is one of the major biotransformation pathways of [6]-shogaol.     

In vitro biotransformation of 3,4-dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran (CR-6), a potent lipid peroxidation inhibitor and nitric oxide scavenger, in rat liver microsomes

The in vitro metabolism of 3,4-dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran (CR-6), a potent lipid peroxidation inhibitor and scavenger of nitric oxide and peroxynitrite species that is currently in phase II trials for antitumoral therapy, has been investigated in rat liver microsomes in the presence of NADP(H). Five major metabolites were identified by comparison with authentic standards, namely, the quinone 2-(3'-hydroxy-3'-methylbutyl-5-methoxy-1,4-benzoquinone (2a) and its ring-closed spiro form oxaspiro[4.5]-2,2-dimethyl-8-methoxy-dec-8-ene-7,10-dione (2b), the hydroquinone 2-(3'-hydroxy-3'-methylbutyl)-5-methoxyhydroquinone (3), the hydroxylated metabolite 3,4-dihydro-4,6-dihydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran (4), and the catechol 3,4-dihydro-6,7-dihydroxy-2,2-dimethyl-1(2H)-benzopyran (5). When the incubations were carried out in the presence of GSH, the HPLC peaks corresponding to the quinone metabolites 2a/b were absent and two novel products were formed showing MS fragmentation patterns consistent with the structure of GSH conjugates of quinone 2a. The time dependence on the formation of metabolites 2a,b and 3 was measured in incubations induced with phenobarbital (PB), dexamethasone, and beta-naphthoflavone (betaNF). For the dexamethasone-induced microsomes, the amount of hydroquinone 3 decreased from minute 10 to minute 30 while that of 2a,b increased in a complementary manner. Similar effects were observed for the incubations carried out using PB- and betaNF-induced microsomes. On the other hand, CR-6 inhibited 7-ethoxyresorufin O-dealkylation activity (IC(50) = 25 microM) in incubations with betaNF-induced microsomes. Likewise, addition of pentoxyresorufin to the incubations of CR-6 with PB-induced microsomes showed a time-dependent inhibition (IC(50)= 75 microM) of the dealkylation activity. These results are in agreement with the putative generation of reactive metabolites from CR-6 that could deactivate P450 1A and P450 2B, respectively. When these incubations were carried out in the presence of 10 mM GSH, the inhibition of P450 2B could be partially prevented. Finally, preincubation of CR-6 with liver microsomes from PB-induced rats resulted in a strong increase in microsomal glutathione S-transferase (mGST) activity (up to a maximum of approximately 5-fold). When the preincubation was carried out in the presence of 10 mM GSH, the activation of mGST was blocked. Overall, these results suggest that CR-6 undergoes in vitro biotransformation indicative of the involvement of thiol-reactive metabolites.     

In vitro metabolism of 2,2',3,4',5,5',6-heptachlorobiphenyl (CB187) by liver microsomes from rats, hamsters and guinea pigs

The metabolism of 2,2',3,4',5,5',6-heptachlorobiphenyl (heptaCB) (CB187) was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 (CYP) inducers, phenobarbital (PB) and 3-methylcholanthrene (MC), was also investigated. In untreated animals, guinea pig liver microsomes formed three metabolites which were deduced to be 4'-hydroxy-2,2',3,5,5',6-hexachlorobiphenyl (M-1), 4'-hydroxy-2,2',3,3',5,5',6-heptaCB (M-2) and 4-OH-CB187 (M-3) from the comparison of GC/MS data with some synthetic authentic samples. The formation rate of M-1, M-2 and M-3 was 18.1, 36.6, 14.7 pmol h-1 mg protein-1, respectively. Liver microsomes of untreated rats and hamsters did not form CB187 metabolites. In guinea pigs, PB-treatment increased M-1 and M-2 significantly to 1.9- and 3.4-fold of untreated animals but did not affect the formation of M-3. In rats, PB-treatment resulted in the appearance of M-2 and M-3 with formation rates of 87.1 and 13.7 pmol h-1 mg protein-1, respectively, but M-1 was not observed. In hamsters, PB-treatment formed only M-2 at a rate of 29.4 pmol h-1 mg protein-1. On the other hand, MC-treatment of guinea pigs decreased the formation of M-1 and M-2 to less than 50% of untreated animals. MC-microsomes of rats and hamsters produced no metabolites. Preincubation of antiserum (300 microl) against guinea pig CYP2B18 with liver microsomes of PB-treated guinea pigs produced 80% inhibition of M-1 and the complete inhibition of M-2 and M-3. These results suggest that PB-inducible CYP forms, especially guinea pig CYP2B18, rat CYP2B1 and hamster CYP2B, are important in CB187 metabolism and that CB187 metabolism in guinea pigs may proceed via the formation of 3,4- or 3',4'-oxide and subsequent NIH-shift or dechlorination.