Pharmacokinetics of bicyclol in rats with acute hepatic failure

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl₄)-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl₄ intoxication in rats. The area under the curve (AUC)_(0–∞), C_max, and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l^?1, 18.8 mg l^?1, and 1.8 l h^?1 kg^?1 in control rats, and 130 mg h l^?1, 33.1 mg l^?1, and 0.15 l h^?1 kg^?1 in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl₄-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.     

Effects of the antimycobacterial compound 2-phenoxy-1-phenylethanone on rat hepatocytes and formation of metabolites

Context: Neolignans are usually dimers formed by oxidative coupling of allyl and propenyl phenols, and the neolignan analogue, 2-phenoxy-1-phenylethanone (LS-2) is a promising antimycobacterial compound showing very weak cytotoxicity in mammalian cells and lack of acute toxicity in murine models.

Objectives: To investigate the mechanism of action of LS-2 in rat hepatocytes by evaluating the activity levels of enzymes related to oxidation status and drug-metabolizing activity.

Materials and methods: Hepatocytes were treated with LS-2 from 0.05 up to 1 mM, for 24 and 48 h, and reduced glutathione (GSH), lipid peroxidation and cytochrome P450 enzyme (CYP450) activity were assayed. A homologous series of phenoxazone ethers were used as substrates to measure the enzymatic profile. The biotransformation of LS-2 was studied in hepatocytes by gas chromatography-mass spectrometry (GC-MS) for detection and analysis of possible metabolites.

Results: Hepatocytes treated with LS-2 up to 1 mM for 24 or 48 h did not induce the formation of GSH and lipid peroxidation. O-Dealkylation activities of the isoenzymes CYP4501A1, CYP4501A2, CYP4502B1 and CYP4502B2 were also not detected in the hepatocytes treated with LS-2 for 24 or 48 h.

Discussion and conclusion: The results indicate that LS-2 or its two detected metabolites, 2-phenoxy-1-phenylethanol and 2,4-(2-hydroxy-2-phenylethoxy)phenol, are not cytotoxic to rat hepatocytes. These compounds maintain a balance between the production of pro-oxidant agents and their respective antioxidant systems. The data show that enzymes related to oxidation status and drug-metabolizing activities are not involved in the mechanism of action of LS-2.     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

克拉霉素对兰索拉唑及其代谢产物在大鼠体内药动学特征的影响

目的研究克拉霉素对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜药动学特征的影响。方法 24只大鼠随机分为4组,分别十二指肠给予兰索拉唑(8 mg·kg^-1)+生理盐水、兰索拉唑(8 mg·kg^-1)+酮康唑(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+反苯环丙胺(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+克拉霉素(8 mg·kg^-1)。于给药后不同时间点采集血样,用LC-MS/MS法测定药物浓度。通过对兰索拉唑及5-羟基兰索拉唑和兰索拉唑砜血药浓度的测定,计算大鼠体内药动学参数。以5-羟基兰索拉唑、兰索拉唑砜与兰索拉唑AUC_0→4h的比值分别作为原药经CYP2C19和CYP3A4代谢程度的指标,研究克拉霉素对兰索拉唑代谢的影响。结果克拉霉素显著增加兰索拉唑的AUC_0→4h、MRT和t_1/2,显著降低其CLz。克拉霉素显著降低兰索拉唑砜与兰索拉唑AUC_0→4h的比值,从0.63±0.17降至0.15±0.09（P<0.05）,兰索拉唑砜的ρ_max显著降低,MRT和t_1/2显著延长。克拉霉素对5-羟基兰索拉唑的药动学参数无明显影响。结论克拉霉素在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用明显,可明显增加兰索拉唑的生物利用度,对临床治疗消化性溃疡有积极意义。     

In vitro drug–drug interaction studies with febuxostat,a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding,identification of metabolic enzymes and cytochrome P450 inhibition

1.?The potential for drug–drug interactions with febuxostat was examined in the following three in vitro systems: the characteristics of the binding of febuxostat to human plasma proteins; identification of the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes participating in the metabolism of febuxostat; and the potential inhibitory effects of febuxostat on typical CYP reactions.

2.?The results have shown that the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat, and that febuxostat did not influence the plasma protein binding of ibuprofen or warfarin. These results indicate that there is little possibility that febuxostat causes a drug–drug interaction by binding to albumin.

3.?The UGT 1 and 2 families were involved in the glucuronidation, and several CYPs participated in the metabolism of febuxostat, suggesting that there is little possibility that the blood concentration of febuxostat varies widely even if febuxostat is concomitantly administered with drugs that inhibit CYP or UGT enzyme. Examination of the inhibitory effect of febuxostat on CYP enzymes suggests that febuxostat minimally inhibits the activities of any CYP.

4.?The results demonstrate that febuxostat is a novel anti-hyperuricaemia drug with low drug–drug interaction potential in clinical use.     

Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat

Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C(max) and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC > or = brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides.     

Time-Dependent Induction of Hepatic Cytochrome P450 Enzyme Activity and mRNA Expression by Bilobalide in Rats

A single dose by gavage of bilobalide (30 mg/kg) was found to produce a time-dependent induction of hepatic cytochrome P450 (CYP) enzyme activity and protein expression in rats. An RT-PCR study further showed that mRNA expression of CYP2B was maximal at 6 h. Plasma and liver bilobalide concentration in rats following administration of Ginkgo biloba extract equivalent to bilobalide of approximately 40 mg/kg showed a similar response to that exhibited by mRNA expression. These findings suggest that bilobalide markedly induced hepatic CYPs, but the induction could be mitigated due to rapid elimination from the liver.     

Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites

AIMS: To investigate the effect of kidney disease on bupropion pharmacokinetics and on cytochrome P450 (CYP) 2B6 activity as measured by bupropion hydroxylation. METHODS: In an open parallel group study, 17 healthy, nonsmoking subjects and 10 patients with impaired kidney function received a single 150 mg oral dose of sustained release bupropion. Plasma concentrations of bupropion and its metabolites were measured for up to 72 h. Subjects were genotyped for the CYP2B6 SNPs 1459 C>T, 785 A>G and 516 G>T. RESULTS: Bupropion AUC was 126% higher (P < 0.0001, 95% CI +72%, +180%), C(max) 86% higher (P = 0.001, 95% CI +40%, +131%), CL/F 63% lower (P = 0.001, 95% CI -29%, -96%), and t(1/2) 140% longer (P = 0.001, 95% CI +76%, +204%) in renally impaired patients. However, only minor changes were detected in the concentrations of the metabolites. In renally impaired subjects the hydroxybupropion : bupropion AUC ratio was decreased by 66% (P = < 0.0001, 95% CI -19%, -114%) and the hydrobupropion : bupropion AUC ratio by 69% (P = 0.001, 95% CI +8%, -146%) compared with controls. CONCLUSIONS: The CL/F of bupropion was significantly lower in subjects with renal impairment. Because the principal metabolites of bupropion possess similar pharmacological activity to the parent compound, dosage recommendations for patients with renal impairment cannot be given. A direct effect of renal impairment on CYP2B6 activity could not be demonstrated by the present study design.     

Down-regulation of hepatic cytochrome P450 enzymes associated with cisplatin-induced acute renal failure in male rats

Hepatic drug metabolism is impaired in experimental animals and humans with renal diseases. An anticancer drug, cisplatin induces acute renal failure (ARF) in rats. Under the same experimental conditions, cisplatin causes down-regulation of hepatic cytochrome P450 (P450) enzymes in an isozyme selective manner. The present study examined the pathological role of ARF in the down-regulation of hepatic P450 enzymes in the cisplatin-treated rats. Male rats with single dose of intraperitoneally cisplatin (5 mg/kg) caused marked changes in renal parameters, BUN and serum creatinine but not hepatic parameters, serum alanine aminotransferase or aspartate aminotransferase. The rats also suffered from down-regulation of hepatic microsomal CYP2C11 and CYP3A2, male specific P450 isozymes, but not CYP1A2, CYP2E1, or CYP2D2. The decrease in serum testosterone level was also observed in injured rats, which was consistent with the selective effects on male specific P450 enzymes. Protection of rats against cisplatin-induced ARF by dimethylthiourea, a hydroxyl radical scavenger, also protected rats against the decrease in serum testosterone levels and the down-regulation of CYP2C11 and CYP3A2. Carboplatin, an analogue to cisplatin but no ARF inducer, did not cause decrease in serum testosterone levels and down-regulation of hepatic male specific P450 enzymes. These results suggest that down-regulation of hepatic P450 enzymes in male rats given cisplatin is closely related to the cisplatin-induced ARF and the resultant impairment of testis function.     

草鱼肝脏细胞色素P450酶系生物转化酪胺生成章鱼胺的研究

目的以草鱼肝脏S-9部位为酶源,以酪胺为原料生物转化生成章鱼胺。方法制备草鱼肝的S-9部位,测定细胞色素P450酶的含量并作生物转化试验。以维生素C为氢载体,异烟肼为单胺氧化酶抑制剂。结果反应1h产生的章鱼胺为879.7μg/4.5mL反应液,章鱼胺的生物合成率为21.4%,酪胺代谢率为90.0%。结论以草鱼肝脏S-9部位为酶源生物转化生成章鱼胺是可行的,但由于P450酶系的非专一性,章鱼胺的生物合成率较低,有待进一步改进。     

肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由Mdr1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有显著的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高     

Modulatory actions of o-coumaric acid on carcinogen-activating cytochrome P450 isozymes and the potential for drug interactions in human hepatocarcinoma cells

Abstract

Context: Although humans are exposed to o-coumaric acid (OCA) in their diet, there is no available literature related to drug interaction and the carcinogen-activating potential of OCA in the HepG2 cell line.

Objective: This study was undertaken to determine the effects of OCA on the cytochrome P450 (CYP) 1A2, CYP2E1, CYP2C9, and CYP3A4 enzymes, which are primarily involved in carcinogen and drug metabolism.

Materials and methods: The cytotoxicity of OCA in HepG2 cells was investigated by measuring the cleavage of WST-1. The protein and mRNA levels of CYPs were determined by western blotting and RT-PCR, respectively.

Results: The EC10, EC25, and EC50 values of OCA were calculated to be 1.84, 3.91 and 7.39?mM, respectively. A sublethal dose of 5?mM was used throughout this study. The CYP1A2 protein and mRNA levels were increased by 52 and 40% (p?<?0.05), as were the CYP2E1 levels by 225 and 424%, respectively (p?<?0.05). However, OCA treatment caused 52 and 60% decreases in the levels of CYP3A4 protein and mRNA (p?<?0.05), respectively. In contrast to CYP3A4, the CYP2C9 protein and mRNA levels increased by 110 and 130%, respectively.

Discussion and conclusion: Co-administration of OCA with some drugs may lead to undesirable food–drug interactions due to modulatory effects on CYP isozymes involved in drug metabolism. Moreover, exposure to OCA may cause an increase in carcinogenicity and toxicity due to the induction of the CYP isozymes involved in chemical carcinogenesis. Therefore, serious precautions should be taken when using OCA as a supplement.     

Metabolism of myclobutanil and triadimefon by human and rat cytochrome P450 enzymes and liver microsomes

Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil was metabolized more rapidly than triadimefon, which is consistent with metabolism of the n-butyl side-chain in the former and the t-butyl group in the latter compound. Human and rat CYP2C and CYP3A enzymes were the most active. Metabolism was similar in microsomes prepared from livers of control and low-dose rats. High-dose (115?mg?kg^?1?day^?1 of triadimefon or 150?mg?kg^?1?day^?1 of myclobutanil) rats showed increased liver weight, induction of total CYP, and increased metabolism of the two triazoles, though the apparent K_m appeared unchanged relative to the control. These data identify CYP enzymes important for the metabolization of these two triazoles. Estimated hepatic clearances suggest that CYP induction may have limited impact in vivo.     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P‐glycoprotein (P‐gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C_max of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P‐gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P‐gp and Cyp3A between the two taxanes. Copyright © 2012 John Wiley & Sons, Ltd.     

The xenobiotic inhibitor profile of cytochrome P4502C8

AIMS: To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A). METHODS: CYP2C8 and NADPH-cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8-catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure. RESULTS: At concentrations of the CYP inhibitor 'probes' employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 microM, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent Ki values of 2.5 microM. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82-91% of control activity) of CYP2C8 at concentrations five-fold higher than the known CYP3A Km. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent Ki values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 microM. CONCLUSIONS: Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.     

The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel

AIMS: Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4). METHODS: This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose. RESULTS: Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel. CONCLUSIONS: According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.     

地非三唑对大鼠肝细胞细胞色素P450 CYP1A1/2的诱导作用

目的 试从mRNA表达水平阐明地非三唑对鼠肝微粒体中细胞色素P450 CYP1A1/2的诱导机制。方法 给SD大鼠腹腔注射地非三唑，采用Trizol法提取大鼠肝脏RNA,用RT-PCR测定经地非三唑处理1, 2及4 d的鼠肝中细胞色素P450 CYP1A1, CYP1A2 mRNA的表达水平。结果 地非三唑处理不同时间的鼠肝细胞中细胞色素P450 CYP1A1, CYP1A2 mRNA的表达水平比空白对照组明显增加，空白对照组CYP1A1吸光度比值为0.270±0.040, 诱导1, 2及4 d的吸光度比值分别为0.343±0.055, 0.417±0.045及0.603±0.083；空白对照组的CYP1A2吸光度比值为0.613±0.189, 而诱导1，2及4 d的吸光度比值分别为1.510±0.226, 3.057±0.518及4.120±0.458。随着诱导时间的增加，细胞色素P450 CYP1A1及CYP1A2 mRNA的表达也逐步增加，诱导时间与表达水平之间存在一定的线性关系,相关系数分别为0.9984和0.9563。结论 地非三唑对细胞色素P450 CYP1A1/2 mRNA表达具有诱导作用。