SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
1 Patients on prolonged treatment with anticonvulsant and phenothiazine drugs exhibited lower than normal concentrations of folate in serum and erythrocytes, and showed increased urinary FIGLU excretion after histidine loading; urinary excretion of D-glucaric acid was also increased suggesting induction of the hepatic microsomal enzymes. 2 Folate deficiency by enzyme-inducing drugs was seen to be determined more by the duration of therapy than by the nature of the drugs. Excretion of FIGLU was increased by 70% by 2-5 years of treatment with anticonvulsant, phenothiazine or tricyclic drugs, and by 200% after 6 or more years. 3 Hepatic microsomal enzyme induction, as measured by D-glucaric acid excretion, was greatest after 2-5 years treatment. 4 It is suggested that the increased requirements for folate, resulting from microsomal enzyme induction, lead to folate deficiency and this subsequently limits enzyme induction, leading to adverse drug side-affects. 5 The dietary folate of hospitalized patients would seem to be generally inadequate for patients on long term treatment with enzyme-inducing drugs.
Enzyme induction by drugs mostly concerns those enzymes involved in drug metabolism: cytochromes P-450, UDP-glucuronosyltransferases, glutathione S-transferases, gamma-glutamyltransferases and epoxide hydrolases. A large variety of molecular forms exists, but not all of them are inducible (e.g. the inducible cytochromes P-450 in man are members of family IA, IIA, IIC, IIE, IIIA). Induction is most common in the liver, but also occurs in other organs (lung, placenta, lymphocytes). Over the past 20 years a relatively small number of drugs and environmental chemicals have been identified as enzyme inducers, perhaps fewer than early studies suggested. Information on inducing properties must be obtained as early as possible during the development of a new drug and made available to clinicians and clinical chemists when the drug is marketed. The main consequences of enzyme induction are changes in pharmacokinetics of the drug itself or of an associated drug. Much progress has been made in methods to identify these inducers.
The effects of colchicine on lysosomal fusion and lysosomal enzyme induction in the cultivated mouse peritoneal macrophage have been examined. Colchicine (10- minus 6 M), but not lumicolchicine, inhibited lysosomal enzyme induction by both phagocytic and pinocytic stimuli. In addition, the drug significantly retarded pinocytic uptake of [3-H] sucrose and transport of the amino acids [3-H] alpha aminoisobutyric acid and L-[3-H] leucine. In contrast, lumicolchicine had no effect on pinocytosis or amino acid transport. Thus, a role for intact microtubules in lysosomal enzyme induction, pinocytosis, and amino acid uptake in these cells is suggested. That colchicine inhibited lysosomal enzyme induction by phagocytic stimuli under conditions in which pinocytosis contributed little to the enzyme rise indicated that inhibition of pinocytosis was unlikely to account for colchicine effects on lysosomal enzyme induction. Effects of colchicine on degradation of phagocytized and pinocytized substrates were examined to determine if intact microtubules are required for fusion among lysosomes, pinosomes, and phagosomes. Colchicine did not alter the rate of intracellular digestion of radiolabeled bacteria by the cultivated macrophage. Similarly, it had no effect on enzymatic hydrolysis of intracellular [3-H] sucrose resulting from uptake of exogenous invertase. The finding that colchicine had no effect on the functional consequences of fusion of lysosomes with endosomes suggests that intact microtubules are not required for fusion among these constituents of the vacuolar apparatus.
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.
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.
Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent.
Homogenates of liver were obtained from control rats and from rats that had received DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane]. The postmicrosomal supernatant fractions were used for the purification of elongation factor 1 by hydroxyapatite chromatography and phosphocellulose chromarography. The amount of binding factor present was essentially the same for both groups of animals, but the specific activity, as measured by the binding assay, was about twice as high in the DDT-treated preparations. After sucrose-gradient sedimentation, the difference in specific activity was found to reside in the low-molecular-weight (50000) form of elongation factor 1. The implications of an increased reactivity of elongation factor 1 during the induction of membrane enzymes are discussed.
A theoretical model is developed for continuous multistage enzymed production systems, which consist of a growth fermentor used for growing microorganisms rapidly without enzyme production and a subsequent system of induction reactors in which enzyme induction and production occurs. The model allows the computation of the fraction of induced cells residing in the induction reactors for organisms exhibiting a lag phase in enzyme induction. For this model a general analytical solution was obtained for the cumulative internal residence time distribution of a series of n well-sterred vessels with a recycle. The theoretical results are compared in a preliminary way with experimentally measured cellulase productivities of continuous multistage cellulose fermentations with Trichoderma viride QM 9414.
We tried to determine whether short-term treatment with alpha-methyldopa, quinidine, digoxin, diazepam or furosemide--drugs in common use in hospitals--is capable of stimulating the activity of hepatic microsomal drug-metabolizing enzymes. Glucaric acid (GA) excretion and serum activity of gamma-glutamyl transpeptidase (GGT) were used as indicators of hepatic microsomal enzyme activity. Increased GA excretion was found in 45% and increased serum GGT activity in 40% of the patients on drug treatment. Only 14.3% showed an increase in both indicators. The excretion of GA rose significantly in patients who received drugs for less than 10 days, as compared with those who received drugs for less than 10 days, whereas the percentage of high GGT values did not rise significantly with increased duration of treatment. The lack of correlation between serum GGT activity and GA excretion casts doubt on the value of GGT as a consistent indicator of microsomal enzyme induction. GA excretion, on the other hand, seems to be a dependable index of microsomal enzyme induction in response to short-term treatment with standard doses of several widely used drugs.
It has previously been suggested that subjects who are initially slow metabolisers of drugs have a greater potential for induction of their drug metabolising enzymes than subjects with initial high rates of metabolism. This inference is based on observations made of changes in half-life of antipyrine. The purpose of this presentation is to reanalyse data previously presented in the literature with reference to clearance, a more precise estimate of drug metabolising activity, and half-life a parameter derived from both clearance and distribution. In one study in non-obese subjects, approximately 80% of intersubject variation in the change of total antipyrine clearance can be explained by differences in body size, particularly differences in liver volume. Furthermore, the relationship between initial antipyrine half-life and the percentage change in antipyrine half-life following induction can be explained by the association between each parameter and body weight. These observations imply that the potential for enzyme induction, and therefore for drug interactions based on enzyme induction, is present in all subjects and that intersubject variance in steady-state drug concentrations are as wide following induction as before induction.
The mechanism of the increase of phosphatidylcholine in liver, accompanying enzyme induction by phenobarbital, has been studied in rats. Using radioactively labeled precursors, the two main pathways of phosphatidylcholine biosynthesis--the CDP-choline pathway and the methylation of phosphatidylethanolamine--were analyzed after pretreatment with 4 doses of phenobarbital (80 mg/kg) on 3 consecutive days. After i.v. injection of choline [Me-3H], choline [Me-14C] or NaH2[32P]O4 the specific radioactivity (sp. act.) of phosphatidylcholine (dpm/nmol) was decreased by 60%, and after methionine [Me-3H] or ethanolamine [1.2-14C] by 40% compared to control rats. These changes are partly due to the increased concentration of phosphatidylcholine and phosphatidylethanolamine, causing the incorporated precursors to dilute, and partly to a secondary effect which leads to a reduction of the sp. act. of free choline in pretreated animals. The concentration of glycerylphosphorylcholine, one of the metabolites of phosphatidylcholine catabolism, was also diminished by almost 50%. From these results it may be concluded that the increase of phosphatidylcholine is due to a retardation of its breakdown rather than to an increase of its synthesis.
Trifluoromethyl derivatives of toluene, phenothiazine, benzimidazole and DDT were administered ip to male rats for 5 days and induction of hepatic microsomal enzymes catalyzing the metabolism of EPN, p-nitroanisole and aminopyrine measured. The addition of a trifluoromethyl substituent to toluene, phenothiazine and benzimidazole increased the inducing capacity of the parent molecule on p-nitroanisole metabolism. Dihalogenation of benzene with trifluoromethyl groups, regardless of position, resulted in induction of p-nitroanisole metabolism whereas halogenation of benzene with trichloromethyl groups did not. For these compounds, the size and electron-inducing capacity of the halogenated substituent may be relative to microsomal enzyme induction.
Concentrations of 6-beta-hydroxycortisol (6-OHF), a polar metabolite of cortisol formed in the endoplasmic reticulum (microsomes) of the liver, and 17-hydroxycorticosteroids (17-OHCS) were measured in the urines of six healthy adult male volunteers exposed to a mean of 9.6 MAC-hours of enflurane anesthesia as an index of possible enzyme induction. The ratio of 6-OHF to 17-OHCS in 24-hour urine specimens collected five days before anesthesia was compared with the ratio of these metabolites in 24-hour urine specimens collected 16 to 18 hours after anesthesia. The ratio of 6-OHF to 17-OHCS increased markedly in five and decreased slightly in one volunteer following anesthesia. The results indicate that enflurane may cause induction of hepatic microsomal enzymes.
A combination of several in vivo parameters has been applied in male healthy volunteers to test the suitability of these parameters to indicate enzyme induction in man: Urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, activity of serum gamma-glut amyltranspeptidase, and pharmacokinetics of aminopyrine respond significantly to phenobarbital treatment. Glucaric acid excretion is enhanced about 7-fold. Its response to induction overcomes the large individual and inter-individual variations which exist in the untreated state for glucaric acid excretion and the other parameters applied, as well. Total body clearance of aminopyrine as obtained after an oral test dose increases more than twofold from 251 to 551 ml/min upon phenobarbital treatment. This arises from increases in both the elimination constant and the apparent volume of distribution, as well. Urinary excretion of aminoantipyrine during 24 hr is about doubled, whereas the elimination of acetyl-aminotipyrine is not much affected. 6 beta-hydroxycortisol excretion in urine and activity of serum gamma-glutamyltranspeptidase are significantly augmented to about 150% of control values. Half life times of phenobarbital measured after termination of treatment are in normal range, suggesting no self-induction of phenobarbital metabolism. Because of the complexity of drug metabolizing enzymes only a combination of different parameters reliably indicates alterations in this enzyme system by inducing agents.
In 12, 24 and 48 hours after a single injection of phenobarbital, barbital-sodium and pentabarbital-sodium in doses of 80 175 an 40 mg/kg respectively an increased synthesis of protein in the cell-free protein-synthetizing system and a rise in the level of cytochromes b5 and P-450 in the liver microsomes of female rats were noted. The maximal changes were registered following introduction of phenobarbital the inducing capacity of barbital-sodium and pentabarbital-sodium twice as low. With chronic introduction of the drugs the tolerance with respect to all of them develops at an equal rate, which excludes the dependence of this phenomenon upon the induction of microsomal metabolizing enzymes of the liver.
The influence of drug stimulated biotransformation on the biological effectiveness of two different contraceptives (Deposition and Gravistat) was observed.--Phenobarbital, a potent enzyme inducer, is known to increase the metabolism of steroid hormones, including estrogens and progrestogens. -- The clinical symptoms of drug mediated enzyme induction of hormonal steroid contraceptives are dysfunctional bleedings. This phenomenon is discussed.
Explore the source record for details and available documents.