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PubMed1984

Enzyme induction and beta-adrenergic receptor blocking drugs.

All beta-adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is only available in man for propranolol, metoprolol and alprenolol. Cross-sectional population studies suggest that environmental factors, such as smoking in the young, are able to influence the oral clearance of propranolol. Long-term studies comparing within-subject clearances of metoprolol, alprenolol and propranolol before and after rifampicin and pentobarbitone, indicate that oral clearance is increased by 50%-500%. Inducing agents can influence intrinsic clearance, liver blood flow, and protein binding in addition to drug metabolising ability, indicating that changes in pharmacokinetic disposition may be complex. Enzyme induction exhibits both dose and time dependency relationships. The maximal extent of enzyme induction is similar between subjects. The range of intersubject variation in drug metabolism is similar before and after induction. The reduction in steady-state beta-adrenergic receptor drug concentration following enzyme induction is sufficiently large that an altered pharmacodynamic response would be expected if no dosage modification is made.

Adolescent↗
PubMed2000

Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme induction.

The use of primary hepatocytes is now well established for both studies of drug metabolism and enzyme induction. Cryopreservation of primary hepatocytes decreases the need for fresh liver tissue. This is especially important for research with human hepatocytes because availability of human liver tissue is limited. In this review, we summarize our research on optimization and validation of cryopreservation techniques. The critical elements for successful cryopreservation of hepatocytes are (1) the freezing protocol, (2) the concentration of the cryoprotectant [10% dimethyl-sulfoxide (DMSO)], (3) slow addition and removal of DMSO, (4) carbogen equilibration during isolation of hepatocytes and before cryopreservation, and (5) removal of unvital hepatocytes by Percoll centrifugation after thawing. Hepatocytes of human, monkey, dog, rat, and mouse isolated and cryopreserved by our standard procedure have a viability > or = 80%. Metabolic capacity of cryopreserved hepatocytes determined by testosterone hydroxylation, 7-ethoxyresorufin-O-de-ethylase (EROD), 7-ethoxycoumarin-O-deethylase (ECOD), glutathione S-transferase, UDP-glucuronosyl transferase, sulfotransferase, and epoxide hydrolase activities is > or = 60% of freshly isolated cells. Cryopreserved hepatocytes in suspension were successfully applied in short-term metabolism studies and as a metabolizing system in mutagenicity investigations. For instance, the complex pattern of benzo[a]pyrene metabolites including phase II metabolites formed by freshly isolated and cryopreserved hepatocytes was almost identical. For the study of enzyme induction, a longer time period and therefore cryopreserved hepatocyte cultures are required. We present a technique with cryopreserved hepatocytes that allows the induction of testosterone metabolism with similar induction factors as for fresh cultures. However, enzyme activities of induced hepatocytes and solvent controls were smaller in the cryopreserved cells. In conclusion, cryopreserved hepatocytes held in suspension can be recommended for short-term metabolism or toxicity studies. Systems with cryopreserved hepatocyte cultures that could be applied for studies of enzyme induction are already in a state allowing practical application, but may be further optimized.

Animals↗
PubMed1984

Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine.

The effect of short-term hepatic enzyme induction with carbamazepine (CBZ) on circulating thyroid hormone concentrations was studied in 10 healthy male subjects. CBZ 400 mg per day was given for 21 days in 6 subjects and for 14 days in a further 4. In the former group the effect of therapy on the pituitary/thyroid axis was also assessed by measuring thyroid stimulating hormone (TSH) response to thyrotrophin-releasing hormone. CBZ therapy resulted in induction of hepatic monooxygenase activity, evidenced by a fall in antipyrine half-life (11.1 +/- 0.7 to 7.6 +/- 0.7 h; p less than 0.001), and a rise in antipyrine clearance (0.72 +/- 0.06 to 0.98 +/- 0.1 ml min-1 kg-1; p less than 0.001). A significant fall in total serum thyroxine (T4) (81.9 +/- 2.9 to 75.1 +/- 2.9 nmol l-1), and triiodothyronine (T3); (1.59 +/- 0.07 to 1.37 +/- 0.05 nmol l-1) and free T4 (16.03 +/- 0.82 to 14.2 +/- 0.8 pmol l-1) was seen after CBZ therapy. (all p less than 0.05). No significant change in reverse T3 or thyroid binding globulin occurred. In the 6 subjects studied for 21 days, maximal changes were found following 14 days' treatment. Basal and stimulated TSH remained unaltered. These effects on circulating thyroid hormone concentrations are likely to be secondary to hepatic enzyme induction leading to accelerated nondeiodinative hepatic hormone disposal. The reason for the failure of pituitary TSH secretion to rise in response to the fall in circulating T4 and T3 is unclear but may have implications for chronic treatment with CBZ in epileptic patients.

Adult↗
PubMed1997

Experimental models for evaluating enzyme induction potential of new drug candidates in animals and humans and a strategy for their use.

Experimental models that have application for evaluating enzyme induction potential have been described in order of increasing complexity. The main focus was on models that have had wide application thus far. However, many new models are currently being developed that may have future applications in evaluating enzyme induction potential. A strategy to evaluate the enzyme induction potential of drug candidates was outlined. This scheme uses a combination of new and established techniques to evaluate data in a stepwise manner that is appropriate to the drug's current stage of development.

Animals↗
PubMed1984

Metabolism of the inhaled anaesthetics: implications of enzyme induction.

Treatment with drugs and exposure to many environmental chemicals results in enzyme induction. However, the clinical significance of increased (or altered) metabolism of the inhaled anaesthetics appears to be trivial. Enzyme induction does not affect the conduct of inhalation anaesthesia. Thus, only delayed organ toxicity is at issue. Since methoxyflurane has fallen into disuse, nephrotoxicity secondary to its administration is no longer a problem. Nephrotoxicity as a result of enhanced defluorination of enflurane or isoflurane is also unlikely: enflurane biotransformation, in most circumstances, is uninducible; isoflurane is metabolized to such a small extent that any increase in its metabolism would be clinically inconsequential. Whether induction of halothane biotransformation and the production of reactive intermediates may lead to hepatoxicity is not yet settled. It is quite clear that induction, in the presence of hypoxia, leads to hepatic necrosis in rats. However, a similar relationship has not been established in surgical patients.

Anesthesia, Inhalation↗
PubMed1987

Pharmacokinetics of chlorpropamide in epileptic patients: effects of enzyme induction and urine pH on chlorpropamide elimination.

The effects of liver enzyme induction and of urine pH on the pharmacokinetics of chlorpropamide have been studied. A single oral dose of chlorpropamide 250 mg was administered to 8 patients on antiepileptic drugs (phenytoin, carbamazepine) and to 8 healthy volunteers. The half-life of chlorpropamide was significantly shorter in the patients (34.4 h) than in the healthy volunteers (50.2 h), but the difference between the groups in the half-life of antipyrine was even more pronounced (5.1 vs 11.4 h). The clearance and volume of distribution of total chlorpropamide were significantly higher in the patients (2.99 ml X h-1 X kg-1 and 126 ml X kg-1) than in the healthy volunteers (1.60 ml X h-1 X kg-1 and 106 ml X kg-1). The unbound fraction of chlorpropamide in serum was also higher in the patients (5.7%) than in the healthy subjects (4.4%). Neither the volume of distribution nor the clearance of the free fraction of chlorpropamide differed significantly between the groups. There was a significant correlation between the half-lives of chlorpropamide and antipyrine, and the half-life of chlorpropamide also had at least as good an inverse correlation with the urinary excretion of unchanged chlorpropamide. The renal clearance of chlorpropamide correlated well with urine pH and was almost 100-fold higher at pH 7 than at pH 5. Both the metabolic and renal clearances of chlorpropamide are important in its elimination. At urine pH higher than 6.5-7, the renal clearance of chlorpropamide represents more than half its total clearance regardless the degree of induction of liver enzymes.

Adult↗
PubMed1979

Antiopyrine half-life as a measure of hepatic enzyme induction: clinical applications in a chronic epileptic population.

Quantitation of hepatic microsomal enzyme induction in epilepsy has a theoretical role in identifying patients at risk of metabolic bone disease, in assessing drug compliance and in predicting anticonvulsant dose/serum level relationships. The clinical usefulness of antipyrine half-life as a measure of enzyme induction in chronic epilepsy has been explored in this study. Mean antipyrine half-life in a control group (mean 10.7 hours SD 2.0) was significantly longer than in an epileptic group (mean 5.6 hours SD 2.3). Antipyrine t1/2 did not distinguish epileptics with osteomalacia from other epileptic patients and half-lives were similar in patients treated with phenytoin and a barbiturate to those in patients on phenytoin alone. No significant correlation was found between antipyrine half-life and phenytoin dose or between half-life and phenytoin level. In 5 patients with low serum levels of anticonvulsant, antipyrine kinetics suggested poor compliance in 3 and rapid hepatic phenytoin degradation in 2. This study suggests that measurement of antipyrine half-life may be useful in assessing drug compliance, but is not useful in predicting the onset of osteomalacia or dose/serum level relationships.

Adult↗
PubMed1985

Liver blood flow and enzyme induction in man.

An increased liver blood flow in rats and monkeys found following induction of the liver microsomal enzyme system by antipyrine and phenobarbitone, formed the basis of the present study in 7 volunteers. The total body clearance of antipyrine, gamma GT, and the urinary excretion of d-glucaric acid and 6-beta-hydroxycortisol were measured. Liver blood flow was estimated after an overnight fast under basal conditions using the 133Xenon inhalation technique. In addition, liver volume was determined by 7 independent investigations using a 99mTechnetium-sulfur-colloid scan of the liver. Afterwards, each volunteer received 1,000 mg antipyrine daily for 14 days and all measurements were repeated. After antipyrine administration the antipyrine half-life decreased significantly from 12.5 to 7.7 hours with an increase of the antipyrine clearance from 34.1 to 50.8 ml/min. In addition, glucaric acid, gamma-GT and 6-beta-hydroxycortisol were significantly increased. Liver blood flow increased from 36.8 ml/min/100 g to 50.9 ml/min/100 g liver (p less than 0.02). The liver volume showed a tendency to increase but was significantly higher in only three of the seven volunteers investigated. The mean liver volumes of 1483 g before and 1585 g after antipyrine administration were not significantly different. In contrast, total liver blood flow increased significantly from 590 ml/min before to 809 ml/min after enzyme induction (p less than 0.02).

Adult↗
PubMed1981

Effect of acute and chronic alcohol ingestion on the rate of folate catabolism and hepatic enzyme induction in mice.

1. Folate deficiency is commonly found in alcoholic subjects although the causative mechanism is uncertain. It has been suggested that microsomal enzyme induction resulting from chronic alcohol ingestion might accelerate the rate of folate catabolism thus causing deficiency. 2. By using an experimental animal model to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of the two urinary catabolites p-[3H]aminobenzoylglutamate and [3H]acetamidobenzoylglumate, we have measured both the rate of folate catabolism and the extent of microsomal-enzyme induction in mice after acute and chronic alcohol ingestion. 3. Despite significant evidence of enzyme induction in the chronic alcohol group, there was no difference in the rate of folate catabolism after acute or chronic alcohol ingestion when compared with that of the controls.

4-Aminobenzoic Acid↗
PubMed1996

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.

Aged↗
PubMed1983

6 beta-hydroxycortisol in random urine samples as an indicator of enzyme induction.

6 beta-Hydroxycortisol (6 beta-OHF) is a major cortisol metabolite formed primarily in the hepatic reticulum by mixed-function oxygenases. Changes in 6 beta-OHF may be used to detect enzyme induction by drugs or disease. Excretion of 6 beta-OHF must be corrected for change in urinary free cortisol (FF) excretion to allow for changes in cortisol production. We report the absence of circadian changes in 6 beta-OHF/FF ratios. Thus random measurements of 6 beta-OHF/FF ratios may be used to detect enzyme induction. This approach greatly simplifies noninvasive screening for enzyme induction.

Child↗
PubMed1978

Lack of parallelism between microsomal enzyme induction and phenobarbital-induced hypercholeresis in the rat.

The relationship between microsomal enzyme induction and the increase in bile flow associated with phenobarbital administration was studied in rats in three experimental situations: examination of the time-course effect of a single dose of phenobarbital (8 mg/100 g body weight) on bile flow and hepatic cytochrome P-450 concentration; study of the influence of SKF 525-A (8 mg/100 g body weight) and cobaltous chloride (6 mg/100 g body weight/day for 3 days) on the phenobarbital-induced hypercholeresis. It was observed that: (a) the maximal increase in bile flow occurred 18 h after the single injection of phenobarbital, while the maximal increase in cytochrome P-450 occurred at 48 h; (b) in rats pretreated with phenobarbital for 3 days, SKF 525-A did not suppress the hypercholeresis due to phenobarbital, and (c) in rats treated with phenobarbital and cobaltous chloride, cytochrome P-450 concentration in the liver was not increased, while bile flow was increased to approximately the same extent as in animals treated with phenobarbital alone. These results further support the hypothesis that microsomal cytochrome P-450-dependent enzyme induction and increase in bile flow are two separate effects of phenobarbital.

Animals↗
PubMedDate not supplied

Estradiol induced vaginal cornification in spayed rats: a model to study hepatic microsomal enzyme induction.

Utilizing vaginal cornification as a response for bioassay, a study was conducted to observe the variation in the median cornification dose (cED50) of estradiol, a hepatic-first-pass candidate, given either ip or sc in spayed rats, with or without enzyme induction by rifampin. Comparisons within and between the groups showed that after enzyme induction cED50 was increased fourfold and cED50 ip/cED50 sc ratio was doubled. The findings clearly demonstrate that this animal model faithfully reflects alterations in hepatic enzyme activity and could serve as an alternate for conventional hexobarbitone sleeping time test to study enzyme induction.

Administration, Oral↗
PubMed2006

A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat.

PURPOSE: To characterize the magnitude, time course, and specificity of phenobarbital (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB. METHODS: PB plasma concentrations and in vitro activities of several CYP enzymes were measured in rats treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: . RESULTS: PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for CYP1A2, CYP3A1/2, and CYP2B1/2, and 3 days for androstenedione producing enzymes. The CYP2C11 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities. CONCLUSION: To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.

Animals↗
PubMed1985

Effect of thyroid hormones on liver microsomal enzyme induction in rats exposed to 2,3,7,8,-tetrachlorodibenzo-p-dioxin.

The effect of thyroidectomy and thyroid hormone replacement therapy on liver microsomal enzyme induction was studied in 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (100 micrograms/kg). Treatment of non-thyroidectomized rats with TCDD had no effect on the concentration of liver microsomal cytochrome b5. In contrast, cytochrome b5 content was increased by TCDD treatment of thyroidectomized rats, regardless of replacement therapy with either T3 or T4. TCDD treatment increased the concentration of cytochrome P-450 (2-3-fold) and the activities of benzo[a]pyrene hydroxylase (4-7-fold), ethoxyresorufin O-de-ethylase (50-70-fold) and UDP-glucuronosyltransferase (5-7-fold) in non-thyroidectomized and thyroidectomized as well as thyroidectomized thyroid hormone treated rats; indicating the induction of these liver microsomal enzyme activities is independent of thyroid status. Because thyroid status alters the toxicity of TCDD but does not alter the ability of TCDD to induce microsomal enzymes, it appears that TCDD toxicity may not be directly related to microsomal enzyme induction.

Administration, Oral↗
PubMed1981

Occupational exposure to halothane results in enzyme induction in anesthetists.

To determine whether exposure to trace concentrations of halothane resulted in enzyme induction, antipyrine pharmacokinetics were measured in six anesthetists before and after ten days of exposure to waste halothane. Antipyrine clearance increased by 29 per cent, a clinically small but statistically significant (P < 0.025) change, whereas the apparent volume of antipyrine distribution remained unchanged, indicating that halothane induces antipyrine metabolism. The implications of this finding for anesthetists cannot be simply defined. Enzyme induction may be beneficial or harmful, depending on the relative toxicities of the unbiotransformed parent compounds and their metabolites.

Air Pollutants, Occupational↗
PubMedDate not supplied

Effect of enzyme induction on bioavailability of hetacillin in patients treated with anticonvulsants and chlorpromazine.

The effect of liver enzyme induction on bioavailability of hetacillin was studied in patients chronically treated with anticonvulsants or chlorpromazine. 24 chronic psychiatric patients classified according to their medication in two groups (anticonvulsants, chlorpromazine) and one group of 11 healthy volunteers, received an i.m. administration of 500 mg hetacillin. Serum levels of ampicillin derived from hetacillin in blood samples taken 2, 4 and 6 hours after the injection were measured and the half-life of the antibiotic was determined for each group. Urinary D-glucaric acid was considered the induction index. Correlation coefficients between the induction index and pharmacokinetic parameters of hetacillin were also determined. Anticonvulsants and chlorpromazine induced the liver microsomal enzymes as demonstrated by the increased D-glucaric acid excretion (P less than 0.001 - P less than 0.05). No statistically significant differences were found in serum levels and half-life of the antibiotic. Correlation coefficients suggest that enzyme induction and hetacillin bioavailability are not significantly related.

Adult↗
PubMed1982

Serum copper concentration and hepatic enzyme induction during long-term therapy with anticonvulsants.

We evaluated hepatic enzyme induction by measuring urinary D-glucaric acid and serum gamma-glutamyltransferase in a group of 40 adult epileptics of both sexes who were receiving long-term treatment with phenobarbital and (or) phenytoin. Total concentrations of copper and ceruloplasmin in their serum and the oxidase activity of ceruloplasmin were significantly greater than in the control group. However, non-ceruloplasmin copper and specific oxidase activity of the ceruloplasmin (activity per gram) were unchanged. A highly significant relationship was found between gamma-glutamyltransferase and (a) copper (r = 0.682, p less than 0.001), (b) ceruloplasmin (r = 0.523, p congruent to 0.001), and (c) the oxidase activity of the ceruloplasmin (r = 0.598, p less than 0.001). There is also a significant correlation of hemopexin with ceruloplasmin (r = 0.531, p congruent to 0.001) and the oxidase activity of the ceruloplasmin (r = 0.598, p less than 0.001). These results suggest that hypercupremia in patients undergoing long-term anticonvulsant therapy is a direct result of hepatic enzyme induction caused by the drugs that induce synthesis of ceruloplasmin.

Adult↗