Sex-related Differences in Rat Liver Microsomal Enzymes and Their Induction by Doxapram

Abstract— The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10–120 mg kg^?1 day^?1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg^?1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg^?1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg^?1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b₅ content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.     

Effects of long-term treatment with dicyclic,tricyclic, tetracyclic,and noncyclic antidepressant drugs on monoamine oxidase activity in mouse brain

• 1.1. The individual long-term effects of the antidepressant drugs zimeldine, viloxazine, imipramine, amitriptyline, nortriptyline, maprotiline, or nomifensine, on brain mitochondrial monoamine oxidase (MAO) activity, were studied in mice that were given daily intraperitoneal injections (30 mg/kg) of these reagents for 4 weeks.
• 2.2. Both the A-form (MAO-A) and B-form (MAO-B) of MAO were inhibited after long-term administration of all the drugs except nortriptyline (MAO-A was not affected) and maprotiline (neither MAO-A nor MAO-B were affected).
• 3.3. Kinetic analysis showed a significant decrease in V_max values, and an increase in K_m values for MAO-B during treatment.
• 4.4. All seven drugs are competitive inhibitors of MAO-A, noncompetitive inhibitors of MAO-B, and were more potent in vitro for MAO-B.
• 5.5. MAO-A was inhibited by the following drugs (in ascending order of potency): nortriptyline, amitriptyline, imipramine, maprotiline, zimeldine, nomifensine, and viloxazine.
• 6.6. MAO-B was inhibited by the following drugs (in ascending order of potency): nortriptyline, imipramine, maprotiline, amitriptyline, zimeldine, nomifensine, and viloxazine.

     

Tyramine infusions and selective monoamine oxidase inhibitor treatment

The relationship between changes in IV tyramine pressor sensitivity accompanying selective monoamine oxidase (MAO) inhibitor treatment and estimates of MAO-A and MAO-B inhibition in vivo were studied. Reductions in platelet MAO activity provided an index of MAO-B inhibition, while changes in plasma 3-methoxy-4-hydroxyphenethylene glycol (MHPG) were used as an hypothesized reflection of MAO-A inhibition. Chronic treatment with the MAO-A inhibitor clorgyline and the MAO-B inhibitor pargyline showed significant inhibition of the alternate MAO enzyme as well, although this crossover effect was greater for pargyline than clorgyline. The MAO-B inhibitor deprenyl appeared to maintain the greatest degree of MAO inhibition selectivity in vivo. Tyramine pressor sensitivity changes accompanying administration of the MAO inhibitors were highly correlated with decreases in plasma MHPG (r=0.92), supporting our previous data indicating the rank order of clorgyline > pargyline > deprenyl for enhancement of tyramine pressor sensitivity and, thus, suggesting that tyramin potentiation is primarily a function of MAO-A rather than MAO-B inhibition. Changes in plasma MHPG are suggested to provide a potentially useful clinical index of in vivo MAO-A inhibition.Presently with the Biological Psychiatry Branch, NIMH     

Further Studies on the Ex-vivo Effects of Procarbazine and Monomethylhydrazine on Rat Semicarbazide-sensitive Amine Oxidase and Monoamine Oxidase Activities

Following administration of the anticancer agent, procarbazine, or one of its metabolites, monomethylhydrazine, to rats, activities of monoamine oxidases A and B (MAO A and MAO B) and of semicarbazidesensitive amine oxidase (SSAO) were measured ex-vivo. Both compounds were found to be potent inhibitors of SSAO in tissue homogenates, exhibiting ID50 values in most tissues of approximately 8 mgkg^?1 (procarbazine) and 0.08 mg kg^?1 (monomethylhydrazine). Concurrent dose-dependent inhibition of MAO activities did not occur. However, in liver, potentiation of MAO B activity, to 140% of that in controls, was apparent following monomethyl-hydrazine and this effect was independent of the drug dose. Both compounds produced a dose-dependent potentiation of MAO A in brown adipose tissue, the elevation being more pronounced following monomethylhydrazine, with activity rising to 350% of that in control homogenates. In a parallel in-vitro study, monomethylhydrazine was without effect on MAO A in brown adipose tissue homogenates. By perfusing the SSAO substrate, benzylamine, through the isolated mesenteric arterial bed of the rat, it was found that pretreatment of animals with procarbazine or monomethylhydrazine reduced metabolism of this amine by a similar degree as had been determined ex-vivo in blood vessel homogenates. The results presented suggest that these compounds would be suitable for use as selective inhibitors in pharmacological examinations of SSAO function in isolated tissues and organs.     

次黄嘌呤对单胺氧化酶的抑制作用

实验证明给小鼠po次黄嘌呤25～500 mg/kg时,对肝和脑中单胺氧化酶B(MAOB)活性的抑制作用与剂量成明显的量—效关系,对MAO-A活性的抑制较弱,且无明显的量—效关系。给小鼠一次po次黄嘌呤500 mg/kg,于给药后16h,对MAO抑制作用最明显。sc时,对肝中MAO活性抑制也以给药后16 h最明显,但对脑中MAO活性抑制不明显。离体实验证明,次黄嘌呤对MAO-B的抑制为竞争性,对MAO-A则为混合型抑制。     

The neuropharmacological profile of N-methyl-N-propargyl-2-aminotetralin: a potent monoamine oxidase inhibitor

Summary N-methyl-N-propargyl-2-aminotetralin (N-0425), a semi rigid analogue of deprenyl was found to be a potent inhibitor of monoamine oxidase type-A and-B. The MAO inhibitory potency was determined in in-vitro, ex-vivo and in-vivo experiments for racemic N-0425 and for both enantiomers, and compared with deprenyl. Racemic N-0425 and (–)N-0425 were found to inactivate both MAO-A and-B to about the same extent in rat brain homogenates, whereas (+)N-0425 was 10 times more potent in inhibiting MAO-B than MAO-A under in-vitro conditions. The latter compound was almost 3 times less active than (–)deprenyl with respect to inactivation of MAO-B. In ex-vivo experiments it was shown that (±)- and (+)N-0425 inhibited rat striatal MAO-B activity almost completely 2 h after a dose of 0.01 mmol/kg ip, whereas both compounds produced a much less rapid inactivation of type-A MAO, which was about 65% after 23 h. No potentiation of the tyramine induced increase in systolic blood pressure was found in normotensive rats following doses up to 0.01 mmol/kg ip of racemic N-0425, but a potentiation was observed after a higher dose of 0.04 mmol/kg. Levels of dopamine and noradrenaline were both increased in rat frontal cortex after the administration of N-0425, which can be interpreted as a reflection of MAO inactivation. Since we were able to select a dose of (±)N-0425 which potently inhibits MAO, without producing a concomittant potentiation of the tyramine effect on blood pressure in normotensive rats, it is reasonable to suggest that this compound, like deprenyl, could be useful in the treatment of Parkinson's disease.Abbreviations used MAO monoamine oxidase - l-DOPA 3,4-dihydroxyphenylalamine - DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - 3-MT 3-methoxytyramine - NA noradrenaline - NM normetanephrine - 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid - PEA -phenylethylamine - N-0425 N-methyl-N-propargyl-2-aminotetralin Some of these results have been presented in a preliminary form at the 5th International Catecholamine Symposium, Göteborg, Sweden, June 12–16, 1983. This work was partly supported by a grant from Nelson Research, Irvine, California, USA     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist,after Enteric Administration in Rat,Cat and Dog

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A_2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg^?1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg^?1 min^?1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg^?1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg^?1, i.v.) by 94% after 10 mg kg^?1 (p.o.) and by up to 74% after 0.3 mg kg^?1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg^?1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg^?1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg^?1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg^?1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A_2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A_2a receptors in the action of adenosine in-vivo.     

The evaluation of isatin analogues as inhibitors of monoamine oxidase

The small molecule, isatin, is a well-known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC₅₀ values of 12.3 and 4.86 μM for MAO-A and MAO-B, respectively. While the interaction of isatin with MAO-B has been characterized, only a few studies have explored structure–activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO-A and MAO-B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC₅₀ < 1 μM. 4-Chloroisatin ( 1b ) and 5-bromoisatin ( 1f ) were the most potent inhibitors with IC₅₀ values of 0.812 and 0.125 μM for MAO-A and MAO-B, respectively. These compounds were also found to be competitive inhibitors of MAO-A and MAO-B with K_i values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5-substitution was particularly beneficial for MAO-B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.     

Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons

Summary Utilizing a specific low substrate concentration technique, intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (–)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (–)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (–)-deprenyl seems to be executed by a metabolite, e. g. l-amphetamine. Taken together, the present electrophysiological and biochemical results show that the neuronal depression of noradrenaline neurones in the LC by MAO-inhibitors is specifically related to the inhibition of MAO-A. Furthermore, the data indicate a relationship between the activity of intrasynaptosomally located MAO-A and the neuronal activity of central noradrenaline pathways.     

Effect of Nifedipine on the Elimination of Theophylline in the Rabbit Subjected to Hypoxia or to an Inflammatory Reaction

This study was performed to assess whether nifedipine could prevent the decrease in hepatic cytochrome P450 induced by acute moderate hypoxia or an inflammatory reaction. Rabbits were subjected Jo acute moderate hypoxia (PaO₂ »37 mmHg), with or without pretreatment with nifedipine (0.5 mg kg^?1 subcutaneously every 8 h, for 48 h). Another group received 5 mL of turpentine subcutaneously with or without pretreatment with nifedipine (0.5 mg kg s.c. every 8 h, for 72 h). The kinetics of 2.5 mg kg^?1 of theophylline were studied in all rabbits up to 8 h, at which time total cytochrome P450 and malondialdehyde were assessed in the liver. Compared with control rabbits, hypoxia and an inflammatory reaction increased theophylline plasma concentrations, as a result of a decrease in theophylline systemic clearance. Both experimental conditions reduced hepatic cytochrome P450 by 40 to 50% and increased hepatic malondialdehyde by approximately 50% (P < 0.05). In control animals, pretreatment with nifedipine did not influence theophylline kinetics, the liver content in cytochrome P450 or malondialdehyde. Pretreatment with nifedipine partially prevented the hypoxia- and the inflammation-induced decrease in liver cytochrome P450; however, nifedipine did not prevent the decrease in theophylline clearance or the increase in liver malondialdehyde. It is concluded that nifedipine affords a partial protection against hypoxia- or inflammation-induced hepatic cellular injury.     

Further studies on the in vivo effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on the liver microsomal drug oxidation system in rats

The effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on microsomal electron transport systems in relation to drug oxidation was studied in rat liver. A single oral dose (250 mg/kg) of NKK-105 increased the ratio of liver to body weight, the microsomal protein content, the cytochrome b₅ content, and the NADPH cytochrome c reductase activity at 24–48 hr after drug administration. The cytochrome P-450 content was decreased at 2–6 hr and slightly increased at 24–48 hr after drug administration. Upon daily administration of NKK-105 at a dose of 250 mg · kg^?1 · day^?1 for 21 days, cytochrome b₅ content and NADPH cytochrome c reductase activity were increased, but cytochrome P-450 content and NADH cytochrome b₅ reductase activity remained unchanged. Despite the increase of NADPH cytochrome c reductase activity, NADPH-dependent lipid peroxidation tended to decrease rather than increase. NADPH stearoyl-CoA desaturase activity increased prior to the increase of cytochrome b₅. Benzphetamine N-demethylase and p-nitroanisole O-demethylase activities were enhanced, accompanied by an increase of cytochrome b₅. Aniline hydroxylase activity was decreased by NKK-105 administration. These results indicate that the induction pattern of liver microsomal electron transport systems by NKK-105 is characteristic.     

Treatment with clorgyline and pargyline differentially decreases clonidine-induced hypotension and bradycardia

Summary A study was made of the effects of acute and chronic treatment with monoamine-oxidase (MAO) inhibitiors on the peripheral and central cardiovascular response induced by clonidine in anaesthetized normotensive rats. Clonidine (30 nmoles · kg^–1 i.v.) produced a biphasic change in mean blood pressure; an initial transient increase was followed by a prolonged hypotensive effect, coinciding with the maximal bradycardia. Twenty-four hours after acute (single) or chronic (daily for 7 days) administration of MAO inhibitors (pargyline 10 mg · kg^–1 SC or clorgyline 0.3 mg · kg^–1 SC) there was no effect either on the basal cardiovascular parameters or on the initial pressor response induced by clonidine. Chronic but not acute treatment with clorgyline, an inhibitor of type A MAO, greatly decreased the hypotension and bradycardia induced by clonidine for as long as 5 days after its discontinuation. On the other hand, after chronic administration of pargyline (10 mg · kg^–1), a preferential type B MAO inhibitor, the hypotension and bradycardia caused by clonidine were differently affected. There was a reduction in the bradycardia up to the third day following the discontinuation of pargyline, whereas the hypotensive response induced by clonidine was only attenuated for 24 h and unaffected with a lower dose of pargyline (0.3 mg · kg^–1).It is concluded that chronic administration of the type A MAO inhibitor, clorgyline, attenuates the central responses to clonidine through the reduction in sensitivity of brain -adrenoceptors. Pargyline, that preferentially inhibits type B MAO, reduces only the bradycardia induced by clonidine. This result may indicate a different modulation of the receptors involved in this response to clonidine.     

A Dapsone-induced Blood Dyscrasia in the Mouse: Evidence for the Role of an Active Metabolite

In the female mouse, dapsone (50–500 mg kg^?1, p.o.) caused a dose-related methaemoglobinaemia which peaked at 0m?5-1 h with recovery to baseline values occurring by 4h. Cimetidine (100 mg kg^?1, p.o.), a known inhibitor of several hepatic P450 isozymes administered 1 h before dapsone, prevented the methaemoglobinaemia. In-vitro, dapsone required activation by mouse hepatic microsomes to cause methaemoglobin formation in mouse erythrocytes and cytotoxicity to human mononuclear leucocytes. In both instances, the toxic effects were markedly reduced by cimetidine. Daily dosing of mice with dapsone (50 mg kg^?1, p.o.) for 3 weeks induced a blood dyscrasia, characterized by a fall of platelet and white blood cell counts, which was inhibited by cimetidine (100 mg kg^?1, p.o. daily). It is concluded that an active metabolite of dapsone arising from a P450-dependent pathway is involved in the genesis not only of the methaemoglobinaemia but also the blood dyscrasia arising from repeated administration of the drug in this species.     

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP⁺), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP⁺ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 µM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 µM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 µM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.     

Selectivity of clorgyline and pargyline as inhibitors of monoamine oxidases A and B in vivo in man

During 4 weeks of treatment with clorgyline, a selective MAO-A inhibitor, platelet monoamine oxidase (MAO) activity was unchanged. During a similar 4-week crossover treatment period with pargyline, a selective MAO-B inhibitor, platelet MAO activity was essentially completely inhibited in the same individuals. The differential effects of the two drugs on platelet MAO, which consists exclusively of the MAO-B form, suggests that the in vitro selectivity of clorgyline, and possibly of pargyline, on MAO-A and MAO-B may be maintained in vivo during long-term administration in man. Reductions in blood pressure, heart rate, and plasma amine oxidase activity were generally similar in magnitude during treatment with both drugs, however, suggesting that either these effects are nonspecific consequences of both MAO-A and MAO-B inhibition, or that pargyline also inhibited MAO-A activity.     

Effect of metadoxine on striatal dopamine levels in C57 Black mice

Abstract— In the present study, we examined the effect of metadoxine on striatal levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in male C57 Black mice. Striatal content was assayed after systemic administration of metadoxine ranging from 1 μg kg^?1 to 500 mg kg^?1. Striatal dopamine increased 1 h after treatment with metadoxine (150 mg kg^?1), but the most notable effect was obtained 24 h after the drug administration. At this time a plateau was reached; the two major metabolites of dopamine showed the same trend. Seven days after metadoxine administration, striatal dopamine approached the control values. Over the same time intervals, striatal 5-HT increased to a lesser extent and 5-hydroxy-indoleacetic acid did not differ significantly from controls. Striatal dopamine increased significantly at a dose of 250 μg kg^?1 up to a dose of 1 mg kg^?1 metadoxine; no further increment was observed between 1 and 500 mg kg^?1 metadoxine. Administration of each component at doses equimolar to 1 mg metadoxine showed that pyridoxine produced only a mild increase in striatal dopamine compared with controls. We suggest that the metadoxine-induced striatal dopamine increase is obtained by increasing synthesis of dopamine.     

The Effect of Indobufen on the Activities of Selected Rat Liver Phase I and Phase II Drug Metabolizing Enzymes,Peroxisomal β-oxidation and Hepatic Glutathione Status

Abstract— Oral administration of indobufen to male rats for three days at daily doses of 5, 10 and 20 mg kg^?1 resulted in no changes in liver total glutathione, cytosolic glutathione S-transferases or microsomal epoxide hydrolase. Reduced glutathione appeared slightly diminished to about 84% of control at the highest dose level. Microsomal cytochrome P450-dependent ethoxyresorufin O-de-ethylase and pentoxyresorufin de-alkylase activities were decreased to 64% (not significantly) and 67% of control at the lowest dose level. 6α- and 7α-Hydroxytestosterone activities were decreased to 67 and 68% of control at the highest dose level. Cyanide-insensitive peroxisomal fatty acid β-oxidation was increased to 223, 261 and 232% of control at doses of 5, 10, and 20 mg kg^?1, respectively. The results obtained in this study are indicative of the action of indobufen as a weak peroxisome proliferator in male rat liver, and suggest a slight but toxicologically insignificant inhibitory action of this drug on microsomal cytochrome P450-dependent enzyme activities.     

Hepatic periportal necrosis induced by chronic administration of cocaine

Cocaine was administered intraperitoneally to male mice at doses of 10, 20 or 30 mg/kg daily for 5 days for periods of 1, 2 and 3 weeks. A dose- and time-dependent periportal hepatic necrosis was noted. The extent of hepatic damage varied from vacuolization of hepatocytes to frank necrosis. No drug-related deaths were noted at any of the dosages studied. The hepatic damage elicited by chronic cocaine was found to be of a transient nature. Chronic cocaine treatment elevated serum glutamicpyruvic transminase levels in a dose- and time-dependent manner. Hepatic cytochrome P₄₅₀ levels were depressed significantly in the 30 mg · kg^?1 · day^?1 dosage group at 1, 2 and 3 weeks. Hexobarbital-induced narcosis was lengthened significantly in the 30 mg · kg^?1 · day^?1 group throughout the course of the study. Chronic administration of cocaine produced a hepatic necrosis that closely resembled that produced by cocaine administered to animals pretreated with stimulators of hepatic metabolism.     

In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner.Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor l-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4 h after administration). Similarly, clorgyline (5 mg/kg) plus l-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461 % of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19–21 h after treatment with l-deprenyl plus clorgyline or l-deprenyl plus brofaromine. At this time, the concentration of 5-HT in the dialysate was increased six-fold in the clorgyline plus l-deprenyl group, as compared to pre-treatment values, but did not differ significantly from these in the brofaromine plus L-deprenyl group. Also, 5-HIAA concentration in the dialyste was still reduced (48% of basal value) in the clorgyline plus l-deprenyl group but not in the brofaromine plus l-deprenyl group. Cortical 5-HT and 5-HIAA concentrations in these animals, measured at the end of the microdialysis experiments (21 h after treatment), displayed changes that paralleled those in the extracellular compartment.These results indicate that: (a) as with clorgyline, the inhibition of MAO-A with brofaromine has a more pronounced effect on tissue 5-HT concentrations than on extracellular 5-HT concentrations; (b) the simultaneous inhibition of both forms of MAO with l-deprenyl and either brofaromine or clorgyline increased the concentration of 5-HT in the dialysate shortly (1–4 h) after administration more than did treatment with either of the MAO-A inhibitors alone; (c) dialysate and tissue 5-HT concentrations were greatly increased one day after the irreversible inhibition of MAO by clorgyline plus l-deprenyl, whereas they had returned to pretreatment values in those animals treated with brofaromine plus l-deprenyl. These transient effects on 5-HT and 5-HIAA in vivo provide further support for the conclusion that the interaction of brofaromine with brain MAO-A is reversible.