Inhibition Of Drug Metabolism Research Articles

BIS (2, 3-dibromopropyl) phosphate nephrotoxicity: Effect of sex and CoCl 2 pretreatment

Bis (2, 3-dibromopropyl) phosphate (BIS-BP) is one of two identified metabolites of Tris (2, 3-dibromopropyl) phosphate (TRIS-BP). We have previously shown that BIS-BP is more acutely nephrotoxic than TRIS-BP. We now report the effect of sex and inhibition of drug metabolism on BIS-BP toxicity. Compared to male rats, age-matched female rats developed less severe and extensive structural damage after BIS-BP. Renal dysfunction, as indexed by serum creatinine and in vitro renal cortical uptake of para-aminohippurate and N-( 14C) methylnicotinamide was similar in males and females. Pretreatment of males with the drug metabolism inhibitor, cobaltous chloride, reduced both functional and structural evidence of BIS-BP toxicity. In separate studies, there was no difference in the distribution of radiolabel in male and female rats three days after administration of 14C-TRIS-BP. These studies showing that female rats are resistant to acute BIS-BP structural damage may explain the previously reported lack of carcinogenicity of TRIS-BP in female rats. The reduction of BIS-BP toxicity by CoCl 2 suggests that unidentified, nephrotoxic metabolites exist and are responsible for part of the nephrotoxicity of BIS-BP.

Species and sex differences in selenium inhibition of hepatic drug metabolism in rodents.

Hepatic microsomal drug metabolism was assessed in male and female rats, mice and hamsters 72 hr after administration of sodium selenite. The greatest inhibitory effect of selenium on hepatic drug metabolism occurred in male rats where the magnitude of reduction in microsomal metabolism by selenium treatment of ethylmorphine and aminopyrine was disproportionately greater than the decrease in either cytochrome P-450 levels or metabolism of aniline. In contrast, the inhibition of metabolism of the three substrates in female mice and the decrease in ethylmorphine-N-demethylase in male mice were similar in magnitude to the reduction observed in cytochrome P-450 content. Hepatic microsomal metabolism in male and female hamsters was relatively resistant to the inhibitory effects of selenium. The inhibition of drug metabolism by selenium may reflect a specific effect of selenium on selected isozymes of cytochrome P-450.

Inhibition of drug metabolism by the antimalarial drugs chloroquine and primaquine in the rat

The effect of the antimalarial drugs chloroquine (CQ) and primaquine (PQ) on rat liver microsomal drug metabolism has been studied in vitro and in vivo. After acute administration, PQ increased pentobarbitone sleeping time in a dose-related manner [control, 94.0 ± 9.4 min; 10mg/kg, 137.0 ± 2.4 min; 20mg/kg, 197.0 ± 7.5 min; 50 mg/kg, 269.0 ± 2.9 min (means ± S.E.M.)], prolonged zoxazolamine paralysis time (control, 140.0 ± 10.0 min; 50 mg/kg, 341.5 ± 25.6 min) and decreased antipyrine blood clearance from 2.17 ± 0.19 to 0.86 ± 0.12 ml/min. CQ showed no effect on pentobarbitone sleeping time or zoxazolamine paralysis time, but decreased antipyrine clearance from 2.17 ± 0.19 to 1.11 ± 0.18 ml/min. Both drugs inhibited aminopyrine N-demethylase activity, although the concentration required to produce 50% inhibition was much greater for CQ (10 mM) than for PQ (approximately 0.1 mM). Lineweaver-Burk plots showed that CQ inhibited competitively whereas PQ inhibition was apparently non-competitive. Ethoxyresorufin O-deethylase activity decreased by about 40 and 50% in the presence of CQ and PQ respectively (250 nM, equimolar with substrate). There was no evidence of induction following chronic administration of CQ and PQ (50 mg/kg/day for 4 days). There was an apparent decrease in cytochrome P-450 content and aminopyrine N-demethylase activity was decreased. These results demonstrate that PQ and CQ inhibit hepatic drug metabolism both in vitro and in vivo and that PQ appears to be the more potent inhibitor.

Inhibition of Drug Metabolism by β-Adrenoceptor Antagonists

The inhibitory effects of β-blockers on the metabolism of antipyrine in man and of lignocaine by rat liver microsomes is studied.

Differential toxicity of trans-permethrin in rainbow trout and mice : I. Role of biotransformation

The trans isomer of [1 R, S] permethrin ( t-per) was > 110 times more toxic to rainbow trout than to mice by both iv and ip administration. The importance of trans-permethrin biotransformation in this differential toxicity was assessed by measuring rates of t-per biotransformation in trout and mouse tissues in vitro, and the effect of inhibitors of drug metabolism on t-per lethality in both species. A previous study had shown that ester hydrolysis by trout liver, plasma, and kidney is much slower than that seen in these same tissues in mice. The present work further indicates that oxidation of t-per is 35 times slower in trout liver microsomes than mouse microsomes when the tissue suspensions were incubated at the body temperature of trout and mice (12°C for trout and 37°C for mice). Inhibition of esterase activity with tri- o-tolyl phosphate (TOTP) produced no potentiation of t-per lethality in trout while the same compound potentiated t-per lethality at least 1.5-fold in mice. Piperonyl butoxide (PIP) alone produced no potentiation in mice but slightly increased t-per toxicity when administered in conjunction with TOTP. PIP caused a slight increase in t-per lethality in rainbow trout but no increase in t-per lethality from control was observed when trout were pretreated with both TOTP and PIP. When drug metabolism was inhibited, t-per was still 65 times more toxic to trout than to mice. The data indicate that trout, in addition to hydrolyzing t-per slowly, also oxidize the compound considerably slower than mice in vitro. Potentiation of t-per lethality by TOTP suggests ester hydrolysis to be an important t-per detoxification reaction in mice but not in trout. However, since t-per was 65 times more toxic to the trout than mouse when drug metabolism was inhibited, other factors, such as differences in target organ sensitivity may be involved in the differential toxicity of permethrin.

Inhibition of drug metabolism by cimetidine in man: dependence on pretreatment microsomal liver function.

The effect of cimetidine on hepatic microsomal drug metabolism was studied in six patients with normal liver and eleven patients with chronic liver disease using the aminopyrine breath test. Before administration of cimetidine, the elimination rate constant of 14CO2 from breath (Kb) was 28.3 +/- SD 1.3%/h in patients with normal liver and 13.5 +/- 7.7%/h in patients with liver disease (P less than 0.001). After 7 days of cimetidine therapy (1 g/day) Kb decreased to 23.3 +/- 5.2%/h (19.0 +/- 13.8% decrease; P less than 0.05) and 7.4 +/- 5.8%/h (50.5 +/- 14.4% decrease; P less than 0.001), respectively. Plasma levels of cimetidine were not significantly different (1.05 +/- 0.14% micrograms/ml v. 0.88 +/- 0.41; P greater than 0.05). The findings indicate that therapeutic doses of cimetidine lead to an inhibition of drug metabolism which is more pronounced in patients with impaired liver function than in liver normals. Therefore, patients with chronic liver disease may be at increased risk with respect to interactions between cimetidine and other drugs which are demethylated by the liver.

In vivo studies on the target tissue metabolism, covalent binding, glutathione depletion, and toxicity of 4-ipomeanol in birds, species deficient in pulmonary enzymes for metabolic activation

Comparative studies on the target organ for covalent binding and toxicity by 4-ipomeanol, a furan derivative metabolically activated by and toxic to the nonciliated bronchiolar epithelial (Clara) cells in mammalian lung, were performed in birds. In birds, whose lungs lack the typical pulmonary ciliated and nonciliated bronchiolar cells and are deficient in enzymes necessary for the metabolic activation of 4-ipomeanol, the target organ for toxicity and covalent binding by 4-ipomeanol was the liver. Tissue damage was not observed in lungs or kidneys of either Japanese quail or roosters at any dose of 4-ipomeanol tested. Likewise, the levels of irreversibly bound 4-ipomeanol metabolites were highest in liver, with much lower levels in lungs, kidneys, and all other organs studied. In addition, toxic doses of 4-ipomeanol markedly depleted hepatic, but not pulmonary or renal glutathione in Japanese quail. The covalent binding of 4-ipomeanol metabolites and concomitant depletion of tissue glutathione in the liver were both time and dose dependent. In quail, over a dose range of 5 to 75 mg/kg, no dose threshold for covalent binding or hepatic damage which depended upon substantial glutathione depletion was observed. Pretreatment of quail with phenobarbital had no effect on liver cytochrome P-450 levels, nor did it have any effect on tissue covalent binding or toxicity by 4-ipomeanol. Although 3-methylcholanthrene pretreatment nearly tripled the microsomal cytochrome P-450 levels in quail liver, it had relatively little or no effect on the hepatic covalent binding or toxicity by 4-ipomeanol. Prior treatment with the drug metabolism inhibitor, piperonyl butoxide, markedly decreased the covalent binding, glutathione depletion, and the toxicity of 4-ipomeanol. Treatment of quail with diethylmaleate produced a dose-dependent depletion of hepatic, renal, and pulmonary glutathione, and it markedly increased hepatic covalent binding by 4-ipomeanol, but had no effect on renal or pulmonary covalent binding. Diethyl maleate markedly enhanced the hepatic necrosis by 4-ipomeanol. The results are consistent with the view that 4-ipomeanol is metabolized preferentially in quail liver to highly reactive metabolites which can be detoxified by glutathione. It appears unlikely however, that differences in detoxification via glutathione are the primary determinants of the remarkable tissue selectivity for covalent binding and toxicity of 4-ipomeanol in different animal species in vivo. The present studies support the view that the tissue selectivity of 4-ipomeanol resides primarily in the ability of the target tissue to rapidly metabolize 4-ipomeanol to its ultimate toxic metabolite(s). These investigations also suggest that the bird may be a potentially useful animal model in studies on the relationship of target organ toxicity to the formation of reactive metabolites by other chemicals requiring metabolic activation.

Cimetidine as an Inhibitor of Drug Metabolism: Therapeutic Implications and Review of the Literature

Cimetidine has been reported to decrease the biotransformation of drugs metabolized by the MFOE system. Additionally, cimetidine decreases liver blood flow and increases the bioavailability of drugs with high hepatic extraction ratios. Patients receiving cimetidine in conjunction with drugs known to interact with cimetidine in conjunction with drugs known to interact with cimetidine are at risk of experiencing toxicity. When appropriate, reducing the dosage of these agents or switching to an alternative drug will minimize the incidence of side effects. Clinicians should be suspicious if patients experience exaggerated drug effects when cimetidine therapy is begun.

Effects of cimetidine and ranitidine on hepatic drug metabolism.

Cimetidine has been shown to impair elimination of a number of drugs metabolized by the hepatic mixed-function oxidase enzymes. It is uncertain whether this is related to its histamine H2-receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2-receptor antagonist and has a completely different structure. Cimetidine (1 gm/day for 7 days) induced a 23% and 35% fall in mean systemic clearance of antipyrine and theophylline, whereas ranitidine (300 mg/day 7 days) had no significant effect on the clearance of either drug. Our data suggest that the inhibition of drug metabolism by cimetidine is not related to histamine H2-receptor antagonism.

Drug interactions with cimetidine.

Because of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs. In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone. Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine. A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism. Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease). Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption. The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.

Drug metabolism by rat and human hepatic microsomes in response to interaction with H2-receptor antagonists

Cimetidine has been reported to decrease plasma clearance of drugs in humans and animals. This reduction in hepatic drug metabolism could be due to cimetidine's intrinsic H2-receptor blocking activity. Alternatively, the imidazole ring structure of cimetidine could explain these observations because imidazole derivatives have been reported to be potent inhibitors of hepatic microsomal drug metabolism. Rat and human hepatic microsomal drug metabolism in the presence of cimetidine and ranitidine, a nonimidazole H2-receptor antagonist, have been studied. High binding affinity of cimetidine for cytochrome P450(Ks = 31 μM) was seen, while no evidence for ranitidine binding to cytochrome P450 was observed. Cimetidine inhibited meperidine and pentobarbital metabolism by both rat and human hepatic microsomes while ranitidine did not affect these two cytochrome P450-mediated biotransformation reactions. Conjugation of morphine, a reaction not mediated by cytochrome P450, was unaffected by either cimetidine or ranitidine. The imidazole structure of cimetidine rather than its H2-receptor blocking activity is primarily responsible for cimetidine-induced inhibition of hepatic drug metabolism.

Interaction of organic dyes with hepatic microsomal drug-metabolizing monoöxygenases in vitro.

Organic dyes such as malachite green, methylene blue, fuchsin, safranine T, neutral red, phenazine methosulphate, riboflavin, dichlorophenolindophenol, phenolphthalein, and fluorescein, inhibit hepatic microsomal mixed-function oxidases and, partly, enhance, partly, inhibit hepatic microsomal NADPH-dependent cytochrome c and neotetrazolium reductases, in contrast to other inhibitors of drug metabolism which do not affect cytochrome c reductase but only interact with cytochrome P-450.

Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man.

Safe therapeutic use of cannabinoids for prolonged periods of time requires an appreciation of pharmacologic actions with both acute and repetitive administration. Cardiovascular effects of acute delta 9-tetrahydrocannabinol (THC) administration included increased sympathetic and reduced parasympathetic tone, although sympathetic reflex responses were impaired. Thus, supine tachycardia and increased blood pressure with upright hypotension are observed. With repetitive dosing, there is a transition from increased to decreased sympathetic activity and from decreased to increased parasympathetic activity, and blood volume substantially increases. As a result, supine bradycardia and decreased blood pressure with tolerance to orthostatic hypotension are observed. Relevance of these observations to management of patients with THC, including considerations of potential drug interactions, is discussed. In other experiments, THC and cannabidiol were found to inhibit metabolism of other drugs (antipyrine and barbiturates) metabolized by liver mixed-function oxidase enzymes. Potential inhibition of drug metabolism must be considered in evaluating responses to chemotherapeutic agents in cancer patients receiving THC and responses to coadministered anticonvulsants in epileptic patients receiving cannabidiol.

Effects of an inhibitor of hepatic drug metabolism, 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A), on thyroxine metabolism in the rat.

We have examined some effects of 2ndash;diethylaminoethyl- 2,2-diphenylvalerate HC1 (SKF 525-A), an inhibitor of hepatic drug metabolism and of cytochrome P-450-mediated reactions, on T4 metabolism by rat liver slices and by rats in vivo. Incubation of liver slices with labeled T4 in medium containing 0.1 mM SKF 525-A reduced deiodination to 27% of control and did not affect T3 formation; at 1.0 mM SKF 525-A, deiodination and T3 formation both declined (to 7% and 60% of control levels, respectively), while degradation of rT3 was not affected. Hypoxia had effects similar to SKF 525-A, i.e. inhibition of T4 deiodination, while formation of T3 from T4 and degradation of rT3 were not inhibited. During a constant infusion of [125I]T4, SKF 525-A (3.5 mg/100 g BW, ip) caused an acute increase in the MCR of T4. It was then found that SKF 525-A added to serum in vitro increased the free T4 fraction; injected in vivo, it caused a prompt rise in the free T4 fraction accompanied by a fall in serum TSH. In rats receiv...

The Mechanism of Anticoccidial Action of Arprinocid-1-N-Oxide

Neither arprinocid nor its liver microsomal metabolite arprinocid-1-N-oxide binds to calf thymus DNA. Neither compound showed an effect on the synthesis of DNA, RNA, or proteins in HeLa cells or on the rate of respiration by Eimeria tenella mitochondria. The 1-N-oxide differs from the parent compound by its toxic effect on HeLa cells (ID50 = 5.0 ppm) reflected primarily through cellular vacuole formation from dilation of rough endoplasmic reticulum structures. Similar vacuole formation was observed in E. tenella merozoites pulse-treated with the drug. This effect on both types of cells is prevented by SKF-525A, an inhibitor of microsomal drug metabolism. Drug-induced visible absorption difference spectra and alterations in the electron paramagnetic signal of rat liver microsomal cytochrome P-450 indicate direct bindings of arprinocid-1-N-oxide to cytochrome P-450. These findings suggest cytochrome P-450 mediated microsomal metabolism involving arprinocid-1-N-oxide as part of the mechanism of antococcidial action of the drug. This metabolism may cause destruction of endoplasmic reticulum leading to cell death.

Lack of effect of vanadyl trichloride on hepatic drug metabolism in the rat

Summary This investigation was undertaken to assess the influence of vanadyl trichloride on drug action in male rats. Following the addition of vanadyl trichloride (2.5×10 −6 M to 2.5×10 −3 M) to rat liver supernatant fractions, significant inhibition of drug metabolism was evident only at vanadium ion concentrations greater than 2.5×10 −4 M. Following in vivo vanadium administration (2 mg V/kg, i.p. for 2 days) duration of pentobarbital hypnosis measured 48 hours later was not significantly prolonged. Brain and plasma concentrations of pentobarbital determined at the time of awakening were not significantly different from controls. Pretreatment with vanadium did not exert any significant effects on hepatic microsomal metabolism of either aniline or p -nitroanisole nor did it alter microsomal levels of cytochrome P-450. These data indicate that vanadyl trichloride is a weak inhibitor of the drug metabolizing enzyme system when added in vitro , but does not alter enzyme activity following in vivo administration.

Reduction of liver blood flow and propranolol metabolism by cimetidine.

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing live blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P less than 0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow.

Selenium antagonism of cadmium-induced inhibition of hepatic drug metabolism in the male rat

Experiments were undertaken to examine the effect of selenium, an essential trace element, on cadmium-induced inhibition of drug metabolism in male, Sprague-Dawley derived rats. Prior administration of sodium selenite (1.6 mg Se/kg, ip) blocked the cadmium-induced (0.84 mg Cd/kg, ip) prolongation of hexobarbital-induced hypnosis and inhibition of hepatic microsomal biotransformation of ethylmorphine or aniline. Selenium also blocked cadmium-induced reduction in microsomal cytochrome P-450 content and the microsomal binding of both ethylmorphine and aniline. However, pretreatment of rats with selenium did not prevent the inhibitory effect of cadmium (10 −6 to 10 −3 m) added in vitro on either ethylmorphine or aniline biotransformation. In addition, the reduction in biotransformation of both substrates following in vivo cadmium administration was not reversed following the in vitro administration of selenium but, in fact, selenium produced further concentration-dependent decreases in drug metabolism. In additional in vitro experiments it was found that the inhibition in drug metabolism induced by in vitro additions of cadmium is not affected by similar additions of selenium when added to the incubation vessel either before or after the cadmium. Thus, for selenium to prevent the cadmium-induced inhibition of hepatic drug metabolism requires in vivo administration of selenium.

Phenytoin--valproic acid interaction in rhesus monkey.

The interaction between phenytoin (PHT) and valproic acid (VPA) was investigated in the rhesus monkey. PHT was given by multiple IV bolus to reach a steady state and then continued while two successive VPA infusions were added. Plasma was assayed for total VPA and PHT as well as free PHT. The addition of VPA produced no change in total PHT levels, a 50% increase in PHT free fraction (increase in free PHT levels), and a decrease in PHT overall elimination rate constant. The increase in free fraction was also documented in a separate in vitro study. The increase in free PHT levels suggested that VPA decreased PHT intrinsic metabolic clearance. This interaction may thus involve a dual mechanism-namely protein binding displacement of PHT and inhibition of PHT metabolism. This mechanism is compatible with other studies showing that VPA is an inhibitor of drug metabolism.

Structure-activity relationships in the inhibitory effects of ellipticines on benzo(a)pyrene hydroxylase activity and 3-methylcholanthrene mutagenicity

The structural features which determine the ability of ellipticine (5,11dimethyl6Hpyrido[4-3b] carbazole) and its derivatives to interact with cytochrome P-450 and to inhibit rat liver microsomal benzo(a)pyrene hydroxylase as well as to inhibit the mutagenicity of 3-methylcholanthrene have been studied. Spectral interactions studies were carried out with either Aroclor 1254-, 3-methylcholanthrene-or phenobarbital-induced microsomes. Inhibitory activities towards benzo(a)pyrene hydroxylase and 3-methylcholanthrene mutagenicity (Ames test), were determined using Aroclor 1254-induced microsomes. It appears that every ellipticine derivative having significant inhibitory effects on hydroxylation of benzo(a)pyrene or mutagenicity of 3-methylcholanthrene also exhibits a very good affinity for microsomal cytochromes P-450. The accessibility of the pyridinic nitrogen of ellipticine derivatives appears as the most important factor for their binding to cytochromes P-450 and the presence of methyl groups in 5 and 11 positions of ellipticine derivatives is an essential condition for the expression of the inhibitory power. Various substitutions in the A ring of ellipticine appear to be of secondary importance. On the other hand the location of the pyridinic ring and consequently the arrangement of the molecule within the hydrophobic pocket of cytochrome P-450 seems also to play an important role in the inhibitory power since isoellipticines are devoid of such properties. These results should help in the design of particularly efficient inhibitors of drug and carcinogen metabolism.