Antipyrine Half-life Research Articles

Differential induction of cytochrome P450 isoforms and peroxisomal proliferation by cyfluthrin in male Wistar rats

Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at β phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the β-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress.

The effect of repeated oral doses of azelastine hydrochloride on antipyrine half-life in normal volunteers.

Treatment with azelastine 4.4 mg twice daily for 21 days did not produce any change in salivary antipyrine elimination in 8 normal volunteers.

Relationship between antipyrine elimination rate constant, clearance and volume of distribution in the rat.

While the relationship between the inverse of antipyrine half-life and clearance has been shown to be approximately linear in man, a recent report indicated that there was no significant relationship between antipyrine elimination rate constant (lambda) and clearance (CL) in the rat. Since this relationship is critical to the use of non-invasive methods to estimate drug metabolizing capacity, we have re-examined the relationship between lambda and CL in the rat. A significant correlation (r = 0.887) was found between antipyrine lambda and CL, while only a weak relationship (r = 0.442) was found between lambda and volume of distribution. These data support the use of non-invasive methods to estimate antipyrine elimination in the rat when invasive methods need to be avoided.

Microsomal enzymes in patients with gastric carcinoma as determined by plasma half-life of antipyrine.

Metabolism of antipyrine was studied in 12 patients with gastric carcinoma and 5 control subjects with peptic ulcer matched for sex, body weight, height, and smoking history. The mean antipyrine half-life was significantly longer (21.5 +/- 1.5 hr) in 3 patients with disseminated gastric carcinoma compared to control subjects (9.3 +/- 1.5 hr) (P less than 0.001). There was no significant difference in the mean antipyrine half-life between 9 patients with localized gastric carcinoma and control subjects. Similarily, the mean metabolic clearance rate of antipyrine was significantly lower (22.8 +/- 5.0 ml/hr/kg) in patients with disseminated gastric carcinoma compared to control subjects (52.6 +/- 13.4 ml/hr/kg) (P less than 0.02). Thus, the presence of gastric carcinoma in humans might alter antipyrine elimination. Significant negative correlation was observed between antipyrine half-life and albumin concentration (r = -0.786, P less than 0.01). These observations indicate that the decrease in antipyrine half-life is not primarily due to the presence of tumor but rather to the nutritional status of an individual.

Comparative disposition of pharmacologic markers for cytochrome P‐450 mediated metabolism, glomerular filtration rate, and extracellular and total body fluid volume of Greyhound and Beagle dogs

The purpose of the study was to compare the disposition of pharmacologic markers for cytochrome P-450 (CYP) metabolism, glomerular filtration rate (GFR), and extracellular (ECFV) and total body fluid volumes (TBFV) of Greyhounds and Beagles. Six healthy Greyhound and six healthy Beagle dogs were studied. Antipyrine, a marker for CYP metabolism and TBFV, and inulin, a marker for the GFR and ECFV, were administered i.v. Samples were collected at predetermined times and plasma was analyzed by validated high-pressure liquid chromatography (HPLC) methods. There were no differences in the disposition or pharmacokinetic parameters for inulin between the dog breeds. However, the clearance of antipyrine (mean = 8.33 mL/min/kg) in Greyhounds was significantly slower than Beagles (13.42 mL/min/kg, P = 0.004). The volume of distribution of antipyrine was significantly larger in Greyhounds (0.789 L/kg) than in Beagles (0.644 L/kg, P = 0.01). The half-life of antipyrine was significantly longer in Greyhounds (1.09 h) compared with Beagles (0.55 h, P = 0.002). The in vitro plasma protein binding of antipyrine was significantly less in Greyhounds (28%) compared with Beagles (40.3%, P = 0.008). Greyhounds exhibited significantly slower CYP metabolism, higher TBFV, and lower in vitro protein binding of antipyrine compared with Beagles. No differences in GFR or ECFV were found.

Antipyrine clearance and metabolite formation in primary biliary cirrhosis.

The disposition of antipyrine is altered and may be a prognostic factor in the presence of various types of hepatic dysfunction. The object of the present study was to investigate whether antipyrine clearance and metabolite formation are useful to detect altered metabolic function in primary biliary cirrhosis. Saliva clearance of antipyrine and the formation clearance of antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) were investigated in a group of 34 women with biopsy-proven PBC (mean age 60 years; range 39-87 years) and in 15 healthy control women (mean age 62 years; range 46-78 years). Parameters of antipyrine clearance of patients in stage I and II were similar to those observed in healthy subjects. When compared to patients in stage I, patients in advanced stages showed a reduction in antipyrine clearance (-29% and -44% in stages III and IV, respectively) and increases in antipyrine half-life (+24% and +75% in stages III and IV, respectively). The reduction in antipyrine clearance was due to a reduction in the formation of all three antipyrine metabolites, with the formation clearance of both HMA and NORA decreasing to a slightly greater extent than that of OHA. Antipyrine clearance correlated significantly with serum bilirubin (P < 0.017) and the Mayo risk score (P < 0.001). Logistic regression analysis indicated that antipyrine clearance was an independent predictor of the histological stage of the disease (P < 0.001). Antipyrine clearance and metabolite formation is a sensitive parameter for assessing hepatic metabolic function in primary biliary cirrhosis.

Effect of experimental fasciolosis on antipyrine metabolism and clearance in water buffaloes

The effect of chronic Fasciola hepatica infection on the metabolism of antipyrine, a marker of microsomal oxidative metabolism, was investigated in male water buffaloes dosed daily with 60 F. hepatica metacercariae over 20 days. The plasma elimination half-life of antipyrine was significantly elevated by 23% at 11 weeks postinfection (p.i.) but did not significantly differ from the control period at 20 weeks p.i. The systemic clearance of antipyrine decreased by 48% at 11 weeks p.i. and then returned to normal. The renal clearance for each of the main antipyrine metabolites decreased at 11 weeks p.i. (hydroxymethylantipyrine (HMA), −42%; norantipyrine (NORA), −58%; and 4-hydroxyantipyrine (OHA), −70%) and did not significantly differ from the control period at 20 weeks p.i. These findings indicate that experimental subclinical fasciolosis leads to altered antipyrine kinetics and to an inhibition of the different antipyrine metabolic pathways in water buffaloes.

Physical exercise and improvement of liver oxidative metabolism in the elderly.

Drug metabolizing capacity is generally reduced in the elderly, and physical exercise has been reported to increase drug oxidative metabolism. The purpose of this investigation was to study the effects of engagement in a program of regular physical exercise on the clearance and metabolite excretion of antipyrine, a marker of oxidative metabolism, in elderly subjects. The saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in 37 elderly women (mean age 66 years). Subjects attended 60-min sessions three times a week for 12 weeks. Each session consisted of both aerobic (training of cardiorespiratory capacity) and nonaerobic (training of muscular strength/endurance and flexibility/coordination) exercises performed at 50-75% of maximum oxygen uptake. Antipyrine was administered orally and pharmacokinetic parameters were obtained from saliva and urine samples. After 3 months of participation in the exercise program, salivary antipyrine clearance was significantly increased by 17% mean (SEM) 0.42 (0.02) vs 0.36 (0.02) ml/min/kg; P < 0.05) and the half-life of antipyrine was significantly reduced by 18% (17.9 (1.1) vs 22.3 (1.3) h; P < 0.05). No significant change with exercise was observed in the renal clearance of antipyrine or in the norantipyrine formation clearance, but significant increases were found for hydroxymethylantipyrine [42 (5) vs 32 (4) microl/kg/min; P < 0.05; +31%] and 4-hydroxyantipyrine [243 (18) vs 194 (17) microl/kg/min; P < 0.05; +25%] formation clearances. These findings indicate that regular exercise leads to increased disposition of antipyrine in the elderly and that the main metabolic pathways of the compound are changed differentially.

The effect of sex on antipyrine metabolism in cattle at different ages.

The aim of this study was to determine the effect of sex on the metabolism of antipyrine by measuring the antipyrine plasma clearance as well as excretion of three major metabolites in urine in cattle of different ages. The experiment was carried out on 10 female and 10 male cattle of Black and White breed. The antipyrine test was carried out at 1, 2, 4, 6, 8, 12 and 18 months of age for each animal (single dose of 10 mg/kg antipyrine were given intravenously). The concentrations of antipyrine, 4-hydroxyantipyrine (4-OHA), 3-hydroxymethylantipyrine (HMA) and norantipyrine (NORA) were measured in plasma and urine by high performance liquid chromatography (HPLC). The apparent volume of distribution of antipyrine (aVd) decreased significantly between 1 and 18 months of age, but mean aVd values observed in males and females were not statistically different. The experimental period was characterised by a steady decrease (statistically significant) in antipyrine half-life (t1/2beta). These values did not differ significantly between males and females under 12 months. In 12 and 18 month-old animals the antipyrine half-life in the females was significantly shorter than in the males. The systemic clearance (Cls) of antipyrine increased significantly between 1 and 18 months of age. No significant differences were observed between systemic clearance of antipyrine in males and females under 12 months. In 12 and 18 month-old animals the Cls values were significantly higher in females than in males. Following intravenous administration, recovery of antipyrine and its three main metabolites increased significantly with age. These values did not differ significantly between males and females under 12 month of age. In 12 and 18 month-old females the excretion of 4-OHA and HMA in urine was significantly higher than in males at the same age. The excretion of NORA and unchanged antipyrine in males and females did not differ significantly. The partial clearances of antipyrine metabolites (Cl(m)) increased significantly between 1 and 18 months of age. No significant differences were observed between Cl(m) values in males and females under 12 months of age. In 12 and 18 month-old females the partial clearances of 4-OHA and HMA were significantly higher than in males. The clearance of NORA was significantly higher in 18 month-old females than in males. In conclusion, we report a sex-linked difference in plasma antipyrine clearance and urinary excretion of the main metabolites of antipyrine in cattle over 12 months of age, the females being the more active metabolizers.

Effect of Zidovudine Therapy in Patients with HIV Infection on Endogenous Interferon Plasma Levels and the Hepatic Cytochrome P450 Enzyme System

In this study, we wanted to investigate if there are differences in endogenous interferon (IFN) plasma levels in patients with different stages of HIV infections before and after therapy with zidovudine (ZDV) and determined the influence of ZDV therapy on the hepatic monooxygenase system by measuring the antipyrine pharmacokinetics. Therefore we investigated the endogenous IFN plasma levels in patients with asymptomatic HIV infection (CDC/WHO A1, n = 10) and patients with AIDS (CDC/WHO C3, n = 10). In AIDS plasma IFN-α and IFN-γ levels are elevated (15.6 ± 5.8 U/ml; 2.1 ± 0.7 U/ml) compared to patients with an asymptomatic HIV infection (6.1 ± 3.3 U/ml; 0.6 ± 0.3 U/ml). The antipyrine clearance was significantly reduced in the group of AIDS patients (43.1 ± 7.2 ml/min compared to 56.4 ± 8.7 ml/min). In a second study with 11 patients in stage CDC/WHO A1/2 and CDC/WHO B/C3 each, we studied the effect of a 14-day administration of ZDV on the endogenous plasma IFN levels and the CYP450 enzyme activity using the antipyrine pharmacokinetics as a parameter. We investigated the antipyrine clearance, clearance to metabolite and half-life by using HPLC. IFNs were measured by RIA or ELISA, respectively. In the first group no significant alterations of antipyrine kinetics or plasma IFN levels were observed after treatment with ZDV. In contrast to these results, we found a significant decrease in IFN-α and IFN-γ (19.8 ± 3.6 U/ml, 4.6 ± 1.5 U/ml before; 7.9 ± 2.6 U/ml, 1.9 ± 1.3 U/ml after administration of ZDV), a decrease in antipyrine half-life, an elevation of the antipyrine clearance (49.8 ± 15.7 ml/min, 57.3 ± 13.7 ml/min) and an elevation of the clearances to metabolite.

The effect of physical conditioning on antipyrine clearance.

The effects of physical conditioning on antipyrine clearance were studied in two groups of subjects. Healthy men not engaged in the systematic practice of any sport were compared with endurance runners (defined as men running > 80 km/week). Studies were carried out at three different periods of the annual plan training at 4-month intervals. Antipyrine was administered orally and pharmacokinetic parameters were obtained from saliva samples by the multiple-sample method. Endurance performance, expressed in terms of the maximal oxygen uptake (VO2max), the ventilatory threshold and the 4-mM x l(-1) lactate threshold (OBLA), was higher in trained than in control subjects at each of the three periods. Antipyrine clearance was also significantly elevated and antipyrine half-life reduced in runners during all periods. No significant difference in VO2max or antipyrine clearance was found between the various periods in either trained or control subjects. Both ventilatory threshold and OBLA increased significantly along the training period in conditioned subjects. Significant correlations were found between antipyrine clearance and VO2max, ventilatory threshold and OBLA. In summary, these results indicate an association between aerobic conditioning and increased hepatic oxidative metabolism of low-clearance drugs.

A Double‐Blind, Placebo‐Controlled Study on the Effect of Vigabatrin on In Vivo Parameters of Hepatic Microsomal Enzyme Induction and on the Kinetics of Steroid Oral Contraceptives in Healthy Female Volunteers

This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of > or = 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-beta-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. VGB treatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/- 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 +/- 3.5 vs. 14.1 +/- 2.1 h), urinary 6-beta-hydroxycortisol excretion (488 +/- 164 vs. 470 +/- 228 nmol/ day), 6-beta-hydroxycortisol-to-cortisol concentration ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransferase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUC, 874 +/- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrel (half-life, 17.7 +/- 5.2 vs. 23.1 +/- 9.8 h; AUC, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 micrograms/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.

The effect of experimental fascioliasis on the pharmacokinetics of antipyrine and sulphadimidine in desert sheep.

Healthy adult male desert sheep were experimentally infected with Fasciola gigantica, to investigate the influence of experimental fasciolasis on the pharmacokinetics of antipyrine and sulphadimidine. Each animal received 500 metacercariae orally. The experimental infection was confirmed histologically, by detection of Fasciola eggs in faeces and by measuring the activities of the enzymes sorbitol dehydrogenase (SD), glutamate dehydrogenase (GD) and aspartate aminotransferase (AST) in plasma during the course of the disease. Changes in the pharmacokinetics of antipyrine and sulphadimidine were reported in the experimentally infected animals. Significant prolongation of antipyrine half life was observed 16 weeks after infection. The half-life of sulphadimidine was also significantly prolonged 5, 9 and 16 weeks after infection. Clearance of the sulphonamide was decreased significantly 5 and 9 weeks after infection and it regained its pre-infection value 16 weeks after infection.

Assessment of Doxylamine Influence on Mixed Function Oxidase Activity upon Multiple Dose Oral Administration to Normal Volunteers

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmaco-kinetics and 6β-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5mg of doxylamine succinate, placebo, or 30mg of phenobarbital administered orally every 6h for 17days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45mL/h/kg) and nonrenal (35 versus 44mL/h/kg) clearances and 6β-hydroxycortisol excretion (338 versus 529 µg) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Effect of spironolactone on antipyrine metabolism in calves

Ten female calves of the Black and White breed aged seven to eight days were studied before and after seven days of treatment with spironolactone at a dose rate of 1 mg kg bodyweight −1 twice a day. The treatment was associated with a statistically significant decrease in the half-life of antipyrine in plasma and an increase in its rate of metabolic clearance. The excretion of 4-hydroxyantipyrine in urine was significantly increased after the treatment with spironolactone, but there were no changes in the rates of excretion of 3-hydroxymethylantipyrine or norantipyrine. These results indicate that spironolactone enhanced the activity of the microsomal drug-metabolising enzyme system and induced cytochrome P-450 in the calves.

Effect of age on the pharmacokinetics of antipyrine in calves

Single doses of 15 mg kg −1 antipyrine were given intravenously to 10 female calves of the black and white breed at one, two, four, six, eight and 12 weeks of age, and the concentrations of antipyrine, 4-hydroxyantipyrine (4- oha), 3-hydroxymethylantipyrine ( hma) and norantipyrine ( nora) were measured in plasma and urine by high performance liquid chromatography. The first three months of life were characterised by a steady decrease in the apparent volume of distribution (aV d) and half-life (t 0.5) of antipyrine. The systemic clearance (Cl s) of antipyrine per unit bodyweight increased significantly between one and 12 weeks of age. Age did not influence the excretion of hma and nora in urine, but the excretion of 4- oha by 12-week-old calves was significantly greater than by one-week-old calves. There was an age-related change in the partial clearances of the antipyrine metabolites when expressed per unit bodyweight.

Absence of hepatic enzyme induction in prostate cancer patients receiving 'Casodex' (bicalutamide).

The potential for hepatic enzyme induction by bicalutamide ('Casodex') was assessed in an open study in prostate cancer patients. A single, oral dose of antipyrine 1000 mg was given before and after 12 weeks' bicalutamide therapy [once daily 50 mg (n = 7) or 150 mg (n = 11)] and its pharmacokinetics and metabolism were determined. Plasma or saliva samples were taken for the measurement of antipyrine concentration. Urine samples were assayed for antipyrine and its three major metabolites. With bicalutamide 50 mg, plasma antipyrine concentrations were maximal between 2 and 4 h after administration, declined in a log-linear manner and were unaffected by bicalutamide therapy; with bicalutamide 150 mg, saliva antipyrine concentrations were maximal between 2 and 4 h, declined in a log-linear manner, and were also unaffected by bicalutamide therapy. Antipyrine half-life was 16.3% shorter after bicalutamide 50 mg (p < 0.05); a small decrease (13.5%) in half-life after bicalutamide 150 mg was not statistically significant. A small reduction (18.6%, p < 0.05) in the AUCinfinity for antipyrine was noted after bicalutamide 150 mg. A statistically significant reduction in antipyrine recovery was seen with the lower bicalutamide dose (23.7%, p < 0.05). The statistically significant changes were small in absolute terms and showed no dose-response relationship. Bicalutamide does not significantly induce the hepatic enzymes responsible for antipyrine metabolism and has no obvious potential for producing clinically significant drug interactions due to enzyme induction.

Effects of aging on antipyrine clearance: predictive factors of metabolizing capacity.

The purpose of this study was to identify variables that can account for the decline of antipyrine clearance (CLAP) in elderly adults and that may help predict a reduction in metabolizing capacity. For comparison, ClAP was determined in 177 elderly (mean age 82 years) and 25 young (mean age 29 years) volunteers. Antipyrine (1 g) was administered orally and ClAP was determined by the one-sample saliva method. Mean ClAP was reduced by 38% and antipyrine half-life increased by 64% in old subjects. Multiple regression analysis of ClAP revealed an independent value for age, serum aspartate transaminase (AST), and height in the elderly. The independent variables collectively accounted for 27% of the variance explained. Age, high serum AST, use of diuretics, and no consumption of drugs known to stimulate oxidative metabolism were selected by multivariate analysis (logistic model) as independent predictors of a low metabolizing capacity. The findings indicate that factors other than age may contribute to impaired hepatic oxidative metabolism in the elderly.

Assessment of antipyrine kinetics from saliva or plasma: influence of age

The purpose of this study was to investigate whether antipyrine estimation in saliva provides valid information on plasma antipyrine clearance (AP Cl) and can be useful as an index of changes in drug metabolism with age. Antipyrine kinetics was studied in 93 elderly (mean age 82 years) and 23 young (mean age 29 years) volunteers. Plasma antipyrine half-life ( APt 1 2 ) increased and plasma AP Cl declined with age. No significant difference between plasma- and saliva-derived parameters was found in either young or old subjects. However, the saliva/plasma AC Cl ratio tended to increase with age. A highly significant correlation between saliva and plasma AP Cl or APt 1 2 was found in young subjects. Values were less closely related in the elderly and the slope of the saliva/plasma AP Cl relationship was significantly different in both groups of subjects. Residual variance was higher in the regressions corresponding to the elderly. The findings in the study indicate that the relationship between saliva and plasma kinetics in young subjects becomes less reproducible with age.

PREDICTION OF DRUG-DRUG INTERACTION CAUSED BY CYP3A INHIBITION: FROM IN VITRO TO IN VIVO, FROM ANIMAL TO HUMAN

Inhibitory effect of E4080 on the cytochrome P450 was studied using laboratory animals in vitro and in vivo.In vitro study E4080 has a high affinity for P450 heme in rat, dog, monkey and human liver microsomes. In rat microsomes, E4080 inhibited testosterone 6β and 16β-hydroxylase which are involved in CYP2B and CYP3A. Using human microsomes, E4080 inhibited metabolism of 7-benzyloxyresolfin, tolbutamide, bufuralol and testosterone. These results suggest that E4080 inhibits CYP 2B6, 2C9, 2D6 and 3A4 in human liver microsomes.In vivo study E4080 prolonged antipyrine half-life and decreased antipyrine clearance in rats, dogs and monkeys at the doses of 10mg/kg which exert pharmacological effect postulated from the minimal effective plasma concentrations(1-2 μg/ml ). The results may be suggested that E4080 interacts with antipyrine metabolism which is thought to be carried out by CYP 1A, 2C and 3A. In the clinical trial E4080 (100mg/man) decreased the excretion of urinary 6β-hydroxycortisol which is a marker of human hepatic cytochrome P4503A induction and inhibition.In conclusion, it is suspected that E4080 inhibits CYP3A not only in animals, but also in human and should be noticed drug-drug interaction in clinical use.