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1.
Objective: Interindividual variations in immunoreactivity and function of three major human drug metabolising P450 monooxygenases has
been investigated in liver microsomes from 42 Caucasians (kidney donors or liver biopsies).
Methods:
Diclofenac 4′-hydroxylation, dextromethorphan O-demethylation and midazolam 1′-hydroxylation, measured by HPLC in incubates,
were used as probes to determine CYP2C9, CYP2D6 and CYP3A4 function kinetics, respectively. Immunoquantification of the three
isoforms was achieved by Western blotting, using rabbit polyclonal antibodies raised against human CYP2C9 and human CYP3A4,
and mouse monoclonal antibody raised against human CYP2D6.
Results:
Diclofenac 4′-hydroxylation exhibited Michaelis-Menten kinetics with k M= 3.4 μmol ⋅l −1 and V max = 45 nmole ⋅mg −1P ⋅h −1. Relative immunoreactivity of CYP2C9 was correlated with V max and CL int.
Dextromethorphan O-demethylation in EM (extensive metabolisers) liver microsomes also showed Michaelis-Menten kinetics, with
k M = 4.4 μmol ⋅l −1 and V max = 5.0 nmol ⋅mg −1P ⋅h −1. Relative immunoreactivity of CYP2D6 was correlated with V max and CL int.
Midazolam 1′-hydroxylation also exhibited Michaelis-Menten kinetics with k M = 3.3 μmol ⋅l −1 and V max = 35 nmol ⋅mg −1P ⋅h −1. Relative immunoreactivity of CYP3A4 was correlated with V max and CL int.
Immunoreactivity and function were correlated for each isozyme, but there was no cross correlation between isozymes.
Conclusion:
The velocity of metabolite formation (V max) by the three major human drug metabolising P450 monooxygenases is correlated with their immunoreactivity in liver microsomes.
Interindividual variation was much larger for V max than k M. Interindividual variability was more pronounced for CYP2D6, probably due to the presence of several different functional
alleles in the population of extensive metabolisers.
Received: 27 December 1995/Accepted in revised form: 29 March 1996 相似文献
2.
Benzene and toluene are common organic solvents currently in worldwide industrial usage, which are metabolized mainly by hepatic
cytochrome P450 2E1 (CYP2E1) in humans. Genetic polymorphism of CYP2E1 in 5′-flanking and coding regions has been found previously in Caucasian and Chinese populations. In this study, the effects
of CYP2E1 alleles causing amino acid substitutions ( CYP2E1*2, CYP2E1*3 and CYP2E1*4; wild-type, CYP2E1.1A) on benzene hydroxylation and toluene methylhydroxylation were studied using recombinant CYP2E1 enzymes of wild-type (CYP2E1.1)
and variants (CYP2E1.2 having Arg76His, CYP2E1.3 having Val389Ile and CYP2E1.4 having Val179Ile) expressed in yeast cells.
The K
m, V
max and CL
int values of CYP2E1.1 were 10.1 mM, 9.38 pmol/min/pmol CYP and 0.99 nL/min/pmol CYP for benzene hydroxylation, and 3.97 mM,
19.9 pmol/min/pmol CYP and 5.26 nL/min/pmol CYP for toluene methylhydroxylation, respectively. The K
m, V
max and CL
int values for benzene and toluene metabolism of CYP2E1.2, CYP2E1.3 and CYP2E1.4 were comparable to those of wild-type CYP2E1.
These findings may mean that the polymorphic alleles of CYP2E1 causing amino acid substitutions are not directly associated with the metabolic activation of benzene and toluene. The information
gained in this study should help to identify the variations in the toxicity of environmental pollutants. 相似文献
3.
It is important to determine the cytochrome P450 (CYP) contribution of certain drugs by taking into consideration the attrition due to issues such as genetic polymorphism and inter-individual variation. In many cases in the early discovery stage, the metabolites of a new chemical have not been identified. Therefore, the present paper devised an approach in which the in vitro intrinsic clearance (CL int) value for new chemicals was determined by measuring substrate depletion. The following prediction methods were compared to calculate CL int using data from recombinant CYP enzymes: (1) the relative CYP content in human liver microsomes; (2) the relative activity factor (RAF) based on the Vmax value; and (3) the RAF value based on the CL int value. The most accurate prediction method was RAF based on CL int. This method would be useful in the early drug-discovery process in cases in which the main metabolite is not identified. 相似文献
4.
In order to evaluate the potential adverse effects due to genetic polymorphism and/or inter-individual variation, it is necessary to calculate the cytochrome P450 (CYP) contribution to the metabolism of new drugs. In the current study, the in vitro intrinsic clearance (CL int) values of marker substrates and drugs were determined by measuring metabolite formation and substrate depletion, respectively. Recombinant CYP microsomes expressing CYP2C9, CYP2C19 and CYP3A4 with co-expressed cytochrome b5 were used, but those expressing CYP1A2 and CYP2D6 did not have co-expressed cytochrome b5. The following prediction methods were compared to determine the CL int value using data from recombinant CYP enzymes: (1) relative CYP enzyme content in human liver microsomes; (2) relative activity factor (RAF) estimated from the Vmax value; and (3) RAF estimated from the CL int value. Estimating RAF from CL int proved the most accurate prediction method among the three tested, and differences in the CYP3A4 marker reactions did not affect its accuracy. The substrate depletion method will be useful in the early drug-discovery stage when the main metabolite and/or metabolic pathway has not been identified. In addition, recombinant CYP microsomes co-expressed with cytochrome b5 might be suitable for the prediction of the CL int value. 相似文献
5.
1. The aim was to compare the metabolic activity of human CYP3A4 expressed in bacteria ( E. coli), yeast ( S. cerevisiae) and human lymphoblastoid cells (hBl), with the native CYP3A4 activity observed in a panel of human livers. 2. Three CYP3A4 substrates were selected for study: dextromethorphan (DEM), midazolam (MDZ) and diazepam (DZ). The substrate metabolism in each of the four systems was characterized by deriving the kinetic parameters Km or S50, Vmax and intrinsic clearance (CL int) or maximum clearance (CL max) from the kinetic profiles; the latter differing by 100-fold across the three substrates. 3. The Km or S50 for the formation of metabolites 3-methoxymorphinan (MEM), 1'-hydroxymidazolam (1'-OH MDZ) and 3-hydroxydiazepam (3HDZ) compared well in all systems. For CYP3A4-mediated metabolism of DEM, MDZ and DZ, the Vmax for hBl microsomes were generally 2-9-fold higher than the respective yeast and human liver microsomes and E. coli membrane preparations, resulting in greater CL int or CL max. In the case of 3HDZ formation, non-linear kinetics were observed for E. coli, hBl microsomes and human liver microsomes, whereas the kinetics observed for S. cerevisiae were linear. 4. The use of native human liver microsomes for drug metabolic studies will always be preferable. However, owing to the limited availability of human tissues, we find it is reasonable to use any of the recombinant systems described herein, since all three recombinant systems gave good predictions of the native human liver enzyme activities. 相似文献
6.
The effects were studied of 4- tert-octylphenol (OP) on hepatic cytochrome P450 enzymes in rats. Rats were treated intraperitoneally with OP twice, at doses
of 5, 10, and 20 mg/kg. Among the cytochrome P450-dependent monooxygenase activities, testosterone 2α-hydroxylase activity,
which is associated with CYP2C11, was significantly decreased by OP at all doses. The level relative to control activity was
67–22%. CYP3A2-dependent monooxygenase, testosterone 6β-hydroxylase activity was also decreased by 51% by OP at 20 mg/kg.
Furthermore, immunoblotting showed that OP (10 or 20 mg/kg) significantly decreased CYP2C11/6 and CYP3A2/1 protein levels.
However, the reduction ratio of CYP2C11/6 and CYP3A2/1 protein levels by OP treatment was lower than that of testosterone
2α-hydroxylase and testosterone 6β-hydroxylase activities. The Cl
int ( V
max/ K
m) value for testosterone 2α-hydroxylase was significantly decreased by OP at all doses, whereas the Cl
int value for testosterone 6β-hydroxylase was only decreased by OP at 20 mg/kg. In addition, 7-ethoxycoumarin O-deethylase activity
was significantly decreased by 32% by the highest dose of OP. By contrast, CYP1A1-, CYP1A2-, CYP2A1-, CYP2B1/2-, CYP2D1-,
CYP2E1- and CYP4A1/2/3- dependent monooxygenase activities were not affected by OP at any dose. These results suggest that
OP changes the male-specific cytochrome P450 isoforms in rat liver, and that these changes closely relate to the toxicity
of OP.
Received: 29 September 1999 / Accepted: 18 October 1999 相似文献
7.
Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxicity and prevention. Metabolism and cytotoxicity of AA and its epoxide glycidamide (GA) were studied in the hepatocytes freshly isolated from male Sprague–Dawley rats. The isolated hepatocytes metabolized AA to GA. The formation of GA followed Michaelis-Menten kinetic parameters yielded apparent K
m = 0.477 ± 0.100 and 0.263 ± 0.016 mM, V
max = 6.5 ± 2.1 and 26.4 ± 3.0 nmol/h/10 6 cells, and CL int = 14 ± 5 and 100 ± 12 μl/h/10 6 cells for the hepatocytes from untreated and acetone-treated rats, respectively. There were lower K
m and marked increases in V
max (fourfold) and in CL int (sevenfold) in acetone-treated rat hepatocytes. The data suggest that CYP2E1 played a major role in metabolizing AA to more toxic GA. Both AA and GA induced a concentration- and time-dependent glutathione (GSH) depletion of the hepatocytes. From decreasing rates of GSH contents in hepatocytes, the parameters of glutathione S-transferase (GST) in hepatocytes to AA and GA were calculated to be K
m = 1.4 and 1.5 mM, V
max = 21 and 33 nmol/h/10 6 cells, and CL int = 15 and 23 μl/h/10 6 cells, respectively. GA 1.5-times more readily depleted GSH content than AA. GA decreased the viability of hepatocytes at 3 mM, but AA did not. These data indicate that GA is more toxic than AA as assessed by intracellular GSH depletion and loss of viability of hepatocytes. GSH precursors such as N-acetylcysteine and methionine provided significant anti-cytotoxic effects on the decrease of GSH content and cell viability of hepatocytes induced by GA and AA. 相似文献
8.
Abstract: Cytochrome P450 2C8 (CYP2C8) plays important roles in the metabolism of various drugs, including the anti‐cancer drug, paclitaxel. We recently identified two novel CYP2C8 alleles ( CYP2C8*13 and CYP2C8*14; wild‐type, CYP2C8*1A) with non‐synonymous single nucleotide polymorphisms in a Japanese population. To precisely investigate the effect of amino acid substitutions ( CYP2C8*13, Ile223Met; CYP2C8*14, Ala238Pro) on CYP2C8 function, CYP2C8 proteins of the wild‐type (CYP2C8.1) and variants (CYP2C8.13 and CYP2C8.14) were heterologously expressed in yeast cells, and their paclitaxel 6α‐hydroxylation activities were determined. The Km, Vmax and CLint values for paclitaxel 6α‐hydroxylation of CYP2C8.1 were 2.3 μM, 4.1 pmol/min./pmol CYP and 1.7 μl/min./pmol CYP, respectively. The Km value of CYP2C8.14 was significantly higher (2.9‐fold) than that of CYP2C8.1. The Vmax value of CYP2C8.14 was comparable to that of CYP2C8.1 and the CLint value was reduced to 46% of CYP2C8.1. In contrast, the Km, Vmax and CLint values of CYP2C8.13 were similar to those of CYP2C8.1. These results suggest that Ala238Pro substitution in CYP2C8.14 decreases the affinity toward paclitaxel of the CYP2C8 enzyme, and that the genetic polymorphism of the CYP2C8*14 allele may influence the clinical response to drugs metabolized mainly by CYP2C8. 相似文献
9.
1.?The aim of this study was to investigate the inhibitory effect of morusin on Glucuronosyltransferase (UGT) isoforms and cytochrome P450 enzymes (CYP450s). We also investigated the metabolism of morusin in human, rat, dog, monkey, and minipig liver microsomes.2.?100?μM of morusin exhibited strong inhibition on all UGTs and CYP450s. The half inhibition concentration (IC 50) values for CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 were 2.13, 1.27, 3.18, 9.28, 4.23, 0.98, and 3.00?μM, and the inhibition kinetic parameters ( Ki) were 1.34, 1.16, 2.98, 6.23, 4.09, 0.62, and 2.11?μM, respectively.3.?Metabolism of morusin exhibited significant species differences. The quantities of M1 from minipig, monkey, dog, and rat were 7.8, 11.9, 2.0, and 6.3-fold of human levels. The Km values in HLMs, RLMs, MLMs, DLMs, and PLMs were 7.84, 22.77, 14.32, 9.13, and 22.83?μM, and Vmax for these species were 0.09, 1.23, 1.43, 0.15, and 0.75?nmol/min/mg, respectively. CL int (intrinsic clearance) values ( Vmax/ Km) for morusin obeyed the following order: monkey?>?rat?>?minipig?>?dog?>?human. CL H (hepatic clearance) values for humans, dogs, and rats were calculated to be 8.28, 17.38, and 35.12?mL/min/kg body weight, respectively.4.?This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species. 相似文献
10.
Case: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism
of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma
was 9.2 (expected MR p: 2.4) and the clearance of maprotiline (CL M) was 4190 ml · min −1 (expected CL M = 1220 in extensive metabolisers of CYP2D6).
Results: The patient's MR urine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication
of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The
therapeutic regimen was changed to coadministration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit
metabolism via CYP2D6. Subsequently, MR p of maprotiline (4.9) and CL M were reduced (1900 ml · min −1; expected CL M in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease.
Conclusion: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible.
As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism
in this patient.
Received: 11 October 1996 / Accepted in revised form: 6 February 1997 相似文献
11.
Chlorpyrifos (CPF), an organophosphorus (OP) pesticide, is bioactivated by cytochrome P450s (CYPs) to the active metabolite chlorpyrifos oxon (CPF-O). Given that human CYP2B6 has the highest intrinsic clearance (CLint) for CPF bioactivation, CYP2B6 polymorphisms may impact human susceptibility to CPF at real world environmental and occupational CPF exposure levels. CYP2B6.4,.5,.7, and .18 were over-expressed in mammalian COS-1 cells to assess the impact of CYP2B6 variants on the Km and Vmax for bioactivation of CPF. Cell lysates were incubated with CPF (0–100 μM) and the production of CPF-O was measured via HPLC analysis. CYP2B6 content was determined by western blot. CYP2B6.18 had neither detectable protein nor activity levels. The Vmax value for each remaining variant was significantly higher than wild-type (CYP2B6.1, Vmax 4.13?×?104 pmol/min/nmol CYP2B6), with CYP2B6.4,.5, and .7 having Vmax values of 4.52?×?105, 1.82?×?105, and 9.60?×?104 pmol/min/nmol CYP2B6, respectively. The Km values for these variants ranged from 0.39 to 1.09 μM and were not significantly different from wild-type. All active variants examined had significantly higher CLint than CYP2B6.1. Variants of CYP2B6 have altered capacity to bioactivate CPF and may affect individual susceptibility by altering the Vmax for CPF-O formation. 相似文献
12.
Objective: Evidence exists to suggest that fluvoxamine is metabolized by CYP1A2. The present study was undertaken in order to further
elucidate the role of CYP1A2 in fluvoxamine disposition.
Methods: Twelve healthy non-smoking male volunteers participated in this cross-over study. Six subjects received first fluvoxamine
50 mg as a single oral dose and, some weeks later, caffeine 200 mg as a single oral dose. The other six subjects received
the drugs in reverse order. Serum concentrations of fluvoxamine, caffeine and paraxanthine were measured and standard pharmacokinetic
parameters were calculated.
Results: There were no significant correlations between caffeine clearance and fluvoxamine oral clearance ( r
s
= −0.30; P = 0.43) or between the paraxanthine/caffeine ratio in serum 6 h after caffeine intake and fluvoxamine oral clearance ( r
s
= −0.18; P = 0.58).
Conclusion: CYP1A2 does not appear to be of major importance in the metabolism of fluvoxamine.
Received: 10 July 1998 / Accepted in revised form: 4 October 1998 相似文献
13.
Abstract1. Prediction of human pharmacokinetics might be made more precise by using species with similar metabolic activities to humans. We had previously reported the species differences in intestinal and hepatic metabolic activities of 43 cytochrome P450 (CYP) substrates between cynomolgus monkeys and humans. However, the species differences between humans and rats or dogs had not yet been determined using comparable data sets with sufficient number of compounds.2. Here, we investigated metabolic stabilities in intestinal and liver microsomes obtained from rats, dogs and humans using 43 substrates of human CYP1A2, CYP2J2, CYP2C, CYP2D6 and CYP3A.3. Hepatic intrinsic clearance ( CLint) values for most compounds in dogs were comparable to those in humans (within 10-fold), whereas in rats, those for the human CYP2D6 substrates were much higher and showed low correlation with humans. In dog intestine, as with human intestine, CLint values for almost all human CYP1A2, CYP2C, CYP2D6 substrates were not determined because they were very low. Intestinal CLint values for human CYP3A substrates in rats and dogs appeared to be lower for most of the compounds and showed moderate correlation with those in humans.4. In conclusion, dogs showed the most similar metabolic activity to humans. 相似文献
15.
Objective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated
in this non-randomized, non-blinded, 7-day, multiple-dose study.
Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL CR >90 ml/min/1.73 m 2, n=9), or patients with either mild (CL CR 61 ml/min/1.73 m 2 to ≤90 ml/min/1.73 m 2, n=9), moderate (CL CR 30 ml/min/1.73 m 2 to ≤60 ml/min/1.73 m 2, n=8), or severe (CL CR <30 ml/min/1.73 m 2, but not on dialysis, n=9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin,
including the area under the concentration–time curve (AUC) 0–24, peak plasma concentration (C max), time to reach C max (t max) and elimination half-life (t 1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance
(ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events,
and laboratory safety indices.
Results: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 μg/h/l vs
19.2 μg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40–60%
higher (30.8 μg/h/l and 29.0 μg/h/l, respectively). C max values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 μg/l, respectively.
This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved
in the United States. The mean t 1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation.
This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient
groups. Furthermore, the mean AUC and C max values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction
to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function.
Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved
without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were
no clinically significant laboratory changes other than those consistent with renal disease.
Conclusion: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal
impairment is likely unnecessary.
Received: 2 August 1999 / Accepted in revised form: 12 January 2000 相似文献
16.
In this study, we have carried out an investigation to determine if chlorzoxazone (CZX) is a suitable probe drug for predicting hepatic injury in carbon tetrachloride (CCl4)-intoxicated rats. The animals received oral doses of CCl4 (0.25, 0.5 and 1 ml/kg) 24 h prior to intraperitoneal administration of CZX. The total CYP and CYP2E1 content, as well as the aniline and CZX hydroxylase activity (Vmax and CLint), was reduced depending on the dose of CCl4 administered. At the highest concentration (128 mM) of diethyldithiocarbamate, a specific inhibitor of CYP2E1, the production of 6-hydroxychlorzoxazone (HCZX) in microsomes from CCl4-treated rats was reduced by about 85%. The IC50 value in microsomes from CCl4-treated rats was between 3 and 5 microM. The production of HCZX and the activity of aniline hydroxylase in CCl4-treated rats correlated with the amount of rat CYP2E1 protein (r=0.881, P<0.001 and r=0.822, P<0.001, respectively). The elimination of CZX by CCl4-treated rats was reduced and the HCXZ production in the CCl4-treated group was less than that in the olive oil-treated control group. The correlations between the intrinsic clearance [CLint: Vmax/Km) in vitro and the total body clearance (CLtot) of CZX hydroxylation and the elimination half-life (t1/2) of CZX in vivo in CCl4-treated rats were high (r=0.839, P<0.001 and r= -0.828, P<0.001, respectively). In addition, the metabolic plasma HCZX/CZX ratio did not require multiple blood sampling and, 2 h after CZX administration in vivo, there was also a high correlation with the CLint (Vmax/Km) in vitro (r= -0.909, P<0.01). In conclusion, these results from this study demonstrate that CZX is a good probe for monitoring the inhibition of metabolism in rats due to CCl4 treatment. 相似文献
17.
The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits
and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found
between plasma amiodarone concentrations in rabbits and volunteers ( r = 0.8263, p < 0.001). Normalized C
max and AUC
0−∞ values were significantly greater in volunteers than rabbits, while specific V
Z and Cl
t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically
significant differences between rabbits and healthy humans. 相似文献
18.
Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4‐hydroxy tolbutamide (4‐OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407‐induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration–time curve ( AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non‐renal clearance ( CLNR). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4‐hydroxylated metabolite formation ratio ( AUC4‐OHTB/ AUCTB) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CLint (by 28.8%) for metabolism of tolbutamide to 4‐OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CLint changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
19.
Objectives: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the
compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK ± cell lines. In
addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1,
and 3A4, were examined.
Results: Carteolol was metabolised to 8-hydroxycarteolol by CYP 2D6 with K M and V max values of 183 μmoles · l −1 and 26.09 pmol · min −1 · pmol −1 P450, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4 were not involved in the metabolism of the compound.
CYP2D6-mediated carteolol 8-hydroxylase activity was inhibited by quinidine, propranolol, nortriptyline, dextromethorphan,
sparteine, bufuralol, and biperiden. Biperiden competitively inhibited the catalytic reaction with a K i value of 0.45 μmoles · l −1. Carteolol did not affect the following catalytic reactions:␣CYP1A2-mediated ( R)-warfarin 6-hydroxylation, CYP2C9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated ( S)-mephenytoin 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation.
Conclusion: 8-Hydroxylation is the only cytochrome P450-catalyzed metabolic reaction of carteolol by its expressed microsomes, and CYP2D6
is the principal isoform of the enzyme involved in the catalytic reaction. Carteolol has neither stimulative nor inhibitory
effects on CYP1A2, 2C9, 2C19, 2E1, and 3A4 activities.
Received: 17 December 1996 / Accepted in revised form: 11 March 1997 相似文献
20.
Purpose The objective of this investigation was to yield a generalized in silico model to quantitatively predict CYP2A6-substrates/inhibitors interactions to facilitate drug discovery.
Methods The newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme was employed to generate the prediction
model based on the data compiled from the literature.
Results The predictions by the PhE/SVM model are in good agreement with the experimental observations for those molecules in the training
set ( n = 24, r
2 = 0.94, q
2 = 0.85, RMSE = 0.30) and the test set ( n = 9, r
2 = 0.96, RMSE = 0.29). In addition, this in silico model performed equally well for those molecules in the external validation sets, namely one set of benzene and naphthalene
derivatives ( n = 45, r
2 = 0.81, RMSE = 0.46) and one set of amine neurotransmitters ( n = 4, r
2 = 0.98, RMSE = 0.32). Furthermore, when compared with crystal structures, the calculated results are consistent with the
published CYP2A6-substrate co-complex structure and the plasticity nature of CYP2A6 is also revealed.
Conclusions This PhE/SVM model is an accurate and robust model and can be utilized for predicting interactions with CYP2A6, high-throughput
screening and data mining to facilitate drug discovery. 相似文献
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