共查询到20条相似文献,搜索用时 46 毫秒
1.
Purpose. The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat.
Methods. 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500µM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/ L) and to study the diazepam-omeprazole interaction in vivo.
Results. The 3-hydroxlation pathway was more prone to inhibition (KIs 108 ± 30 and 28 ± 11 µM in microsomes and hepatocytes, respectively) than the demethylation pathway (KIs of 226 ± 76 and 59 ± 27 µM in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive with Km/KI ratios larger than 1 for the 3HDZ pathway and smaller than 1 for the NDZ pathway. There was an omeprazole concentration dependent decrease in diazepam clearance in vivo which could be modelled using a simple inhibition equation with a KI of 57µM (19.8mg/L). In contrast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole.
Conclusions. The in vivo KI for the omeprazole: diazepam inhibition interaction shows closer agreement with the KI values obtained in hepatocytes than with those observed in microsomes. 相似文献
2.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(7):592-597
Abstract1. The present study evaluates which factors should be incorporated into a simplified approach to reasonably predict CYP3A-mediated drug–drug interaction (DDI) at an early drug discovery stage.2. CYP3A IC50 values were obtained using human liver microsomes (HLM) and hepatocytes. Plasma and microsomal protein binding and in vitro hepatocyte partition coefficient (Kp) were also determined for 10 drugs. Therapeutic human maximum plasma concentrations (Cmax) were retrieved from the literature. DDI predictions were performed using an equation incorporating the fraction of the substrate metabolized by CYP3A with the total or free plasma Cmax, with or without correction for hepatocyte Kp.3. Based on the Ki data from HLM, the use of total Cmax provided a prediction of DDI within 2-fold of the observed clinical values for 9 out of 10 drugs.4. In comparison, free drug corrections for both Cmax and Ki values from HLM led to an underprediction of DDI (>3-fold error for five drugs).5. Data from hepatocytes showed, in general, lower prediction accuracy than data from HLM.6. CYP3A-mediated DDIs can be predicted with a high level of accuracy based on Ki estimates from HLM data and the total therapeutic plasma Cmax of the inhibitors. This approach should be widely applicable to the assessment of clinically significant DDIs risk in early drug discovery programs 相似文献
3.
BACKGROUND AND PURPOSE
Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.EXPERIMENTAL APPROACH
Itraconazole (20 mg·kg−1) and metformin (100 mg·kg−1) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (Vmax), Michaelis–Menten constant (Km) and intrinsic clearance (CLint) for the disappearance of each drug, apparent inhibition constant (Ki) and [I]/Ki ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.KEY RESULTS
After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration–time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.CONCLUSIONS AND IMPLICATIONS
The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2. 相似文献4.
In vitro inhibition and induction of human cytochrome P450 enzymes by SIPI5357, a potential antidepressant
下载免费PDF全文
![点击此处可从《Biopharmaceutics & drug disposition》网站下载免费的PDF全文](/ch/ext_images/free.gif)
This study investigated the in vitro drug–drug interaction potential of SIPI5357, an arylalkanol‐piperazine derivative used in the treatment of depression. Drug–drug interaction occurs via inhibition or induction of enzymes involved in their metabolism. In human liver microsomes, SIPI5357 showed the strongest inhibition of CYP2D6, followed by CYP3A4 (testosterone) and CYP2C8. Inhibition was observed in a concentration‐dependent manner, with IC50 values of 18.45 µM, 36.63 µM (CYP3A4/testosterone), 89.23 µM, respectively. SIPI5357 was predicted not to cause significant metabolic drug–drug interaction via inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP3A4 (midazolam) because the IC50 values for these enzymes were both >100 µM (200 times maximum plasma concentration [Cmax]). SIPI5357 showed a mixed model inhibition of CYP2D6 (Ki = 11.12 µM). The value of [I]/Ki for CYP2D6 inhibition by SIPI5357 is below the FDA cut‐off value of 0.1; it is therefore reasonable to assume that SIPI5357 will not cause significant CYP2D6 inhibition. However, positive controls (50 µM omeprazole and 25 µM rifampin) caused the anticipated CYP induction, but the highest concentration of SIPI5357 (5 µM; 10 times plasma Cmax) had a minimal effect on CYP1A2 and CYP3A4 mRNA levels in freshly isolated human hepatocytes, suggesting that SIPI5357 is not an inducer of these enzymes. However, significant induction of CYP2B6 was observed at 0.5 µM and 5 µM. In conclusion, SIPI5357 might cause drug–drug interaction via induction of CYP2B6. The in vivo drug–drug interaction potential deserves further investigation. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
5.
M Ishigami K Kawabata W Takasaki T Ikeda T Komai K Ito Y Sugiyama 《Drug metabolism and disposition》2001,29(7):1068-1072
Taking into account the species and sex differences in drug interactions based on the inhibition of cytochrome P450 (P450)-mediated drug metabolism, we examined whether the interaction between simvastatin and itraconazole observed in humans could also occur in rats, the most commonly used animal species for pharmacokinetic studies. Itraconazole inhibited the in vitro metabolism of simvastatin in female rat liver microsomes, but not in male rat liver microsomes. Using anti-P450 antisera, the main P450 isozyme responsible for the metabolism of simvastatin was identified as CYP3A in female rats and CYP2C11 in male rats. Therefore, the sex difference in the inhibition of simvastatin metabolism by itraconazole seems to be caused by a difference in the P450 isozymes responsible for the metabolism of simvastatin in male and female rats and the different ability of itraconazole to inhibit CYP3A and CYP2C11. In addition, the effect of itraconazole on the pharmacokinetics of simvastatin in rats was also investigated. The area under the curve value of simvastatin was increased approximately 1.6-fold by the concomitant use of itraconazole (50 mg/kg) in female rats, whereas in male rats, itraconazole had no effect. In conclusion, it was found that the results obtained in male rats did not reflect the results in humans as far as the inhibition of simvastatin metabolism by itraconazole was concerned. The P450 isozymes involved in the metabolism of drugs should be taken into consideration when rats are used as a model animal for humans in the investigation of drug interactions. 相似文献
6.
C. S. Cook L. M. Berry E. Burton 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(3):215-228
1.?The inhibition kinetics of eplerenone (EP) 6β-hydroxylation by 10 drugs were determined in vitro using human liver microsomes. Inhibition factors were calculated from in vitro inhibition constant (Ki) and three different inhibitor Cmax values (liver Cmax of total and unbound inhibitor, and maximum influx concentration of inhibitor into the liver). Subsequently, the inhibition factors were compared with available pharmacokinetic data derived from clinical interaction trials conducted by Pfizer involving EP and these drugs. EP was also evaluated for its effect on the metabolism of 10 drugs in vitro, and again the in vitro data were compared with results from the clinical trials.2.?The Ki values for the inhibition of EP 6β-hydroxylation by cisapride, cyclosporine, digoxin, erythromycin, fluconazole, ketoconazole, midazolam, saquinavir, simvastatin and verapamil were 2.90, 1.24,>75.0, 9.50, 59.0, 0.160, 8.10, 0.546, 6.23 and 13.3?μM, respectively. Among the three methods, inhibition factors (Rb) calculated using the Ki and estimated liver Cmax values of the unbound drug were best correlated with the in vivo area under the curve-fold increases of EP in humans. The Rb values for the drugs listed above were 1.04, 1.69, 1.00, 2.17, 2.24, 4.90, 1.00, 1.82, 1.01 and 1.04, respectively, and the in vivo area under the curve-fold increases of EP by these drugs were 1.04, 1.16, 0.930, 2.87, 2.24, 5.39, 1.00, 2.07, 1.03 and 1.98, respectively.3.?EP did not have any significant effects on the drugs tested in vitro or in the clinic.4.?Using in vitro metabolic interaction data, human in vivo pharmacokinetic interactions involving EP could be predicted nearly quantitatively. The lack of effects of EP on the pharmacokinetics of other drugs in man was also suggested in the in vitro data. 相似文献
7.
M. Miura T. Ohkubo 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(11-12):1001-1011
1. The study was carried out to identify and characterize kinetically the cytochrome P450 (CYP) enzymes responsible for the major metabolite formation of quazepam.2. In in vitro studies using human liver and intestinal microsomes and cDNA-expressed human CYP and FMO isoenzymes, quazepam was rapidly metabolized mainly by CYP3A4 and to a minor extent by CYP2C9, CYP2C19 and FMO1 to 2-oxoquazepam (OQ), which was then further biotransformed to N-desalkyl-2-oxoquazepam (DOQ) and to 3-hydroxy-2-oxoquazepam (HOQ) mainly by CYP3A4 and CYP2C9. CYP3A4 is the enzyme predominantly responsible for all the metabolic pathways of quazepam.3. Itraconazole inhibited the formation of OQ from quazepam, HOQ from OQ and DOQ from OQ in human liver microsomes with Ki values of 8.40, 0.08 and 0.39?μM, respectively. However, the Ki for OQ formation was greater than the peak plasma itraconazole concentration following a clinically relevant 200-mg oral dose to healthy volunteers. In addition, CYP2C9 and CYP2C19 inhibitors failed to inhibit OQ formation from quazepam.4. In conclusion, clinically relevant drug interaction with CYP inhibitors seem unlikely for the major metabolic pathway of quazepam to OQ. 相似文献
8.
T. Kanazu Y. Yamaguchi N. Okamura T. Baba M. Koike 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(5):403-413
1.?Cytochrome P450 (CYP) 3A catalysis of testosterone 6β-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80?mg?kg?1?day?1 dexamethasone (DEX) for 3 days.2.?Midazolam was mainly metabolized by CYP3A in DEX-treated female rat liver microsomes from an immuno-inhibition study, and the apparent Km was 1.8?μM, similar to that in human microsomes.3.?Ketoconazole and erythromycin, typical CYP3A inhibitors, demonstrated extensive inhibition of midazolam metabolism in DEX-treated female rat liver microsomes, and the apparent Ki values were 0.088 and 91.2?μM, respectively. The values were similar to those in humans, suggesting that DEX-treated female rat liver microsomes have properties similar to those of humans.4.?After oral administration of midazolam, the plasma midazolam concentration in DEX-treated female rats significantly decreased compared with control female rats. The area under the plasma concentration curve (AUC) and elimination half-life were one-11th and one-20th of those of control female rats, respectively.5.?Using DEX-treated female rats, the effect of CYP3A inhibitors on midazolam pharmacokinetics was evaluated. The AUC and maximum concentration in plasma (Cmax) increased when ketoconazole was co-administered with midazolam.6.?It was shown that the drug–drug interaction that occurs in vitro is also observed in vivo after oral administration of midazolam. In conclusion, the DEX-treated female rat could be a useful model for evaluating drug–drug interactions based on CYP3A enzyme inhibition. 相似文献
9.
Objective: The affinity of (+)-, (−)- and (±)-fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for
specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms
of lovastatin, pravastatin and simvastatin.
Methods:
Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac
4′-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1′-hydroxylation (CYP3A4).
Results:
Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated Ki > 50 μmol⋅l−1). Racemic and (+)- and (−)-fluvastatin showed moderate affinity (estimated Ki > 50 μmol⋅l−1) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated Ki < 1 μmol⋅l−1). Diclofenac 4′-hydroxylation was competitively and stereoselectively inhibited, with measured Ki’s of 0.06 and 0.28 μmol⋅l−1 for (+)- and (−)-fluvastatin, respectively.
Conclusion:
Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active)
showing 4–5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants)
may be expected.
Received: 9 June 1995/Accepted in revised form: 7 November 1995 相似文献
10.
Kiyomi Ito Koji Chiba Masato Horikawa Michi Ishigami Naomi Mizuno Jun Aoki Yasumasa Gotoh Takafumi Iwatsubo Shin-ichi Kanamitsu Motohiro Kato Iichiro Kawahara Kayoko Niinuma Akiko Nishino Norihito Sato Yuko Tsukamoto Kaoru Ueda Tomoo Itoh Yuichi Sugiyama 《The AAPS journal》2002,4(4):53-60
When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I]u/Ki ratio, where [I]u is the unbound concentration around the enzyme and Ki is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I]u/Ki ratio using literature data. The maximum concentration of the inhibitor in the circulating blood ([I]max), its maximum unbound concentration in the circulating blood ([I]max,u), and its maximum unbound concentration at the inlet to the liver ([I]in,max,u) were used as [I]u, and the results were compared with each other. In order to calculate the [I]u/Ki ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported Ki values determined in in vitro studies using human liver microsomes. For most of the drugs with a calculated [I]in,max,u/Ki ratio less than 0.25, which applied to about half of the drugs investigated, no in vivo interactions had been reported or “no interaction” was reported in clinical studies. In contrast, the [I]max,u/Ki and [I]max/Ki ratio was calculated to be less than 0.25 for about 90% and 65% of the drugs, respectively, and more than a 1.25-fold increase was reported in the area under the concentration-time curve of the co-administered drug for about 30% of such drugs. These findings indicate that the possibility of underestimation of in vivo interactions (possibility of false-negative prediction) is greater when [I]max,u or [I]max values are used compared with using [I]in,max,u values. 相似文献
11.
T. TERAMURA Y. FUKUNAGA E. J. VAN HOOGDALEM T. WATANABE S. HIGUCHI 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(9):885-900
1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N -debenzylated product (M-1), a hydrolyzed product of the benzylpyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. InvolvementofCYP3Ainthethree primarymetabolic pathways was revealedbythe following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies.Thesecondarymetabolites, M-2 and M-4 (pyridine forms of M-1 and M-3),were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 μM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC50 for the latter drugs was estimated to be > 200, 200 and 20 μM respectively, which was roughly > 200,6000 and 50 times higher than their respective therapeutic plasma levels,suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance. 相似文献
12.
Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (Ki) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The Ki values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the Ki value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the Ki values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4. 相似文献
13.
Context: Friedelin is a triterpenoid with several biological activities. However, the affects of Friedelin on the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.Objective: This study investigates the inhibitory effects of Friedelin on the major human liver CYP isoforms (CYP3A4, 1A2, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8).Materials and methods: First, the inhibitory effects of Friedelin (100?μM) on the eight human liver CYP isoforms were investigated in vitro using human liver microsomes (HLMs), and then enzyme inhibition, kinetic studies, and time-dependent inhibition studies were conducted to investigate the IC50, Ki and Kinact/KI values of Friedelin.Results: The results indicate that Friedelin inhibited the activity of CYP3A4 and 2E1, with the IC50 values of 10.79 and 22.54?μM, respectively, but other CYP isoforms were not affected. Enzyme kinetic studies showed that Friedelin is not only a noncompetitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2E1, with Ki values of 6.16 and 18.02?μM, respectively. In addition, Friedelin is a time-dependent inhibitor of CYP3A4 with Kinact/Ki value of 4.84?nM/min.Discussion and conclusion: The in vitro studies of Friedelin with CYP isoforms suggested that Friedelin has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4 and 2E1. Further clinical studies are needed to evaluate the significance of this interaction. 相似文献
14.
Toshiyuki Kudo Yuya Ozaki Tomomi Kusano Eri Hotta Yuka Oya Seina Komatsu 《Xenobiotica; the fate of foreign compounds in biological systems》2016,46(3):241-246
Abstract1.?Buffer conditions in in vitro metabolism studies using human liver microsomes (HLM) have been reported to affect the metabolic activities of several cytochrome P450 (CYP) isozymes in different ways, although there are no reports about the dependence of CYP2C8 activity on buffer conditions.2.?The present study investigated the effect of buffer components (phosphate or Tris-HCl) and their concentration (10–200?mM) on the CYP2C8 and CYP3A4 activities of HLM, using paclitaxel and triazolam, respectively, as marker substrates.3.?The Km (or S50) and Vmax values for both paclitaxel 6α-hydroxylation and triazolam α- and 4-hydroxylation, estimated by fitting analyses based on the Michaelis–Menten or Hill equation, greatly depended on the buffer components and their concentration.4.?The CLint values in phosphate buffer were 1.2–3.0-fold (paclitaxel) or 3.1–6.4-fold (triazolam) higher than in Tris-HCl buffer at 50–100?mM. These values also depended on the buffer concentration, with a maximum 2.3-fold difference observed between 50 and 100?mM which are both commonly used in drug metabolism studies.5.?These findings suggest the necessity for optimization of the buffer conditions in the quantitative evaluation of metabolic clearances, such as in vitro–in vivo extrapolation and also estimating the contribution of a particular enzyme in drug metabolism. 相似文献
15.
Physiologically based pharmacokinetics model predicts the lack of inhibition by repaglinide on the metabolism of pioglitazone
下载免费PDF全文
![点击此处可从《Biopharmaceutics & drug disposition》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Purpose: Repaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study was to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro, in silico and in vivo. Method: In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE‐PBPK linked model was built with Simcyp®. Then, a randomized, 2‐phase cross‐over clinical study was conducted in 12 healthy volunteers. Results: Repaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki = 0.0757 µm ), [I]/Ki > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of pioglitazone in clinical trials showed no significant difference between these two treatment groups (p > 0.05). Conclusion: Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo, which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and to the high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
16.
Jun-Sheng Wang Xia Wen Janne T. Backman Pivi Taavitsainen Pertti J. Neuvonen Kari T. Kivist 《Basic & clinical pharmacology & toxicology》1999,85(6):157-161
Abstract: The inhibitory effects of five calcium channel blockers (diltiazem, isradipine, mibefradil, nifedipine and verapamil) and three azole antifungal agents (itraconazole, hydroxyitraconazole and ketoconazole) on the α-hydroxylation of midazolam, a probe drug for CYP3A4-mediated interactions in humans, were studied in vitro using human liver microsomes. IC50 and Ki values were determined for each inhibitor. The kinetics of the formation of α-hydroxymidazolam were best described by simple Michaelis-Menten kinetics. The estimated values of Vmax and Km were 696 pmol min.?1 mg?1 and 7.46 μmol l?1, respectively. All the compounds studied inhibited midazolam α-hydroxylation activity in a concentration-dependent manner, but there were marked differences in their relative inhibitory potency. Ketoconazole was the most potent inhibitor of midazolam α-hydroxylation (IC50 0.12 μmol l?1), being 10 times more potent than itraconazole (IC50 1.2 μmol l?1). The inhibitory effect of hydroxyitraconazole (IC50 2.3 μmol l?1) was almost as large as that of itraconazole. Among the calcium channel blockers, mibefradil was the most potent inhibitor of the α-hydroxylation of midazolam, with an IC50 value (1.6 μmol l?1) similar to that of itraconazole. The other calcium channel blockers were much weaker inhibitors than mibefradil: verapamil exhibited a modest inhibitory effect with an IC50 of 23 μmol l?1, while isradipine, nifedipine and diltiazem, with IC50 values ranging from 57 to >100 μmol l?1, were weak inhibitors. This rank order of potency against the α-hydroxylation of midazolam was verified by the Ki values. With the exception of diltiazem, these in vitro results conform with the observed interaction potential of these agents with midazolam and many other CYP3A4 substrates in vivo in man. 相似文献
17.
ContextPeucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy.ObjectiveThe interaction between peucedanol and CYP450s was investigated.Materials and methodsPeucedanol (0, 2.5, 5, 10, 25, 50, and 100 μM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro.ResultsPeucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.03, 13.57, and 7.58 μM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a Ki value of 4.07 μM and a competitive inhibitor of CYP1A2 and 2D6 with a Ki values of 3.39 and 6.77 μM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the Ki/Kinact value of 5.44/0.046 min/μM.Discussion and conclusionsIn vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation. 相似文献
18.
It is likely that a proportion of people treated with the anti-schistosomicidal drug praziquantel (PZQ) is also taking other drugs such as chloroquine (CHQ), a widely used anti-malarial. The effect of CHQ on the pharmacokinetics and metabolism of PZQ in rats and in humans was therefore studied. CHQ decreased the bioavailability of PZQ and reduced its maximum serum concentrations to a significant extent in rats and in humans. The clearance was increased to a statistically significant extent in rats but not in humans because of the wide interindividual variation. The effect of CHQ on PZQ pharmacokinetics was unexpected since drugs that inhibit hepatic drug metabolism usually increase the bioavailability of PZQ. We found that CHQ inhibits non-competitively the metabolism of PZQ to its major metabolite, 4-hydroxy-praziquantel, with a Ki of 1.65 mM in rat hepatic microsomes. Maximum concentrations attained by CHQ in serum, however, are low compared to the Ki value and significant inhibition is therefore unlikely in vivo. The explanation for CHQ's effect on the pharmacokinetics of PZQ may be due to other effects of CHQ rather than to a direct effect on drug-metabolizing enzymes. 相似文献
19.
Abstract: The elimination of felodipine in liver microsomes from dog and man were characterized by Km and Vmax. The results were compared with previous data reported for rat. In all species studied, felodipine was primarily metabolized to its corresponding pyridine analogue. The elimination rate order was rat> dog> man. The same species difference was observed in vivo for the oral plasma clearance which was; rat 26 1/hr/kg, dog 7.5 1/hr/kg and man 4.3 1/hr/kg. The intrinsic hepatic clearance of felodipine was predicted in vitro from Vmax over Km. The in vitro values were not significantly different from those observed in vivo. Felodipine is a high-clearance drug and the in vivo extraction ratios were about the same in all species: rat 0.80, dog 0.83 and man 0.84. The extraction ratios predicted from the in vitro studies, rat 0.91, dog 0.70 and man 0.80, agreed well with those observed in vivo. 相似文献
20.
Comparison of CYP3A Activities in a Subclone of Caco-2 Cells (TC7) and Human Intestine 总被引:2,自引:0,他引:2
Raeissi Shamsi D. Guo Zuyu Dobson Glenn L. Artursson Per Hidalgo Ismael J. 《Pharmaceutical research》1997,14(8):1019-1025
Purpose. To compare the activity of the CYP3A enzyme expressed by TC7, a cell culture model of the intestinal epithelial cell, to the activity of human intestinal CYP3A4, using terfenadine as a substrate.
Methods. The metabolism of terfenadine was investigated in intact cells and microsomal preparations from TC7, human intestine, and liver. The effect of two CYP3A inhibitors, ketoconazole and troleandomycin (TAO), on the metabolism of terfenadine was also examined.
Results. Only hydroxy-terfenadine was detected in TC7 microsomal incubations. In contrast, azacyclonol and hydroxy-terfenadine were detected in human intestinal and hepatic microsomal incubations. The Km values for hydroxy-terfenadine formation in TC7 cells, intestine and liver microsomes were 1.91, 2.5, and 1.8, M respectively. The corresponding Vmax values were 2.11, 61.0, and 370 pmol/min/mg protein. Km values for azacyclonol in intestinal and hepatic samples were 1.44 and 0.82 M and the corresponding Vmax values were 14 and 60 pmol/min/mg protein. The formation of hydroxy-terfenadine was inhibited by ketoconazole and TAO in human intestine and TC7 cell microsomes. The Km and Vmax values for terfenadine metabolism in intact TC7 cells were similar to those from TC7 cell microsomes.
Conclusions. Our results indicate that TC7 cells are a potentially useful alternative model for studies of CYP3A mediated drug metabolism. The CYP3A expressed by TC7 cells is not CYP3A4, but probably CYP3A5, making this cell line suitable for studies of colonic drug transport and metabolism. 相似文献