Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative

Plasma concentrations of the major metabolites of 450191-S, a new sleep inducer which is a 1H-1,2,4-triazolyl benzophenone derivative, were determined in rats. Under the HPLC conditions employed, several major metabolites were detected in plasma, and thus the plasma concentration-time profiles for these metabolites were checked in rats in various states. When the animals were pretreated with high doses of 450191-S (200 or 600 mg/kg for 5 or 3 days, respectively) to induce hepatic drug-metabolizing enzymes, plasma concentrations of the metabolites after oral administration of a dose of 200 mg/kg of 450191-S decreased markedly depending on the induced enzyme activity. Pretreatment of rats with phenobarbital also caused decreased plasma levels of metabolites, which were almost the same as those in 450191-S-pretreatment. On the other hand, administration of beta-naphthoflavone to rats led to higher plasma levels of metabolites, and slower elimination compared with those in the control and 450191-S- or phenobarbital-pretreated rats. These results indicate that plasma levels of metabolites are regulated by the drug-metabolizing enzymes in the liver. It also suggests the participation of some specific forms of cytochrome P-450 in the biotransformation of 450191-S and its metabolites.     

Pharmacology of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (II). Sleep-inducing activity and effect on the motor system

The sleep-inducing activity and effect on the motor system of the 1H-1,2,4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for 1 to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the dorsal root potential of the rat; it particularly acted on the crossed extensor reflex in the same manner as the commercial BDZ sleep inducers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of low-dose phenobarbital on hepatic microsomal UDP-glucuronyl transferase activity

To determine whether hepatic microsomal enzyme induction occurs in rats following administration of phenobarbital at doses similar to those used in humans (0.5 to 7.5 mg/kg), UDP-glucuronyl transferase (UDPGT) and cytochrome P-450 activities were measured in liver homogenate and microsomal preparations from control rats and rats treated for 6 days with phenobarbital at 1 and 3 mg per kg per day. While no significant increases in liver weight and protein content of homogenate and microsomal preparations were observed with either dose of the drug, both UDPGT and P-450 activities were enhanced significantly following administration of phenobarbital at 3 mg per kg per day. The activity of P-450 was increased by approximately 30% and that of UDPGT by 15-24 and 45-66%, respectively, employing bilirubin and p-nitrophenol as the acceptor substrate. The extent of induction of bilirubin or p-nitrophenol UDPGT was similar when measured with "native" enzyme or with enzyme activated by UDP-N-acetyl glucosamine, digitonin or deoxycholate. These data suggest that the discordant effects of phenobarbital on UDPGT and cytochrome P-450 previously reported in humans and rats may not be attributable solely to differences in the drug doses employed.     

Xenobiotic imprinting of the hepatic monooxygenase system. Effects of neonatal phenobarbital administration

The ability of phenobarbital (PB) to neonatally "imprint" or "program" the hepatic microsomal cytochrome P-450-dependent monooxygenase system (MOS) was investigated. Phenobarbital (30 mg/kg) was administered subcutaneously to neonatal rats of both sexes on days 1-5 postpartum. Various hepatic MOS activities were measured at 6, 22, 50 and 140 days of age. Six-day-old animals of both sexes displayed the increased hepatic microsomal protein levels and enzyme activities expected from the action of phenobarbital as a transitory MOS inducer. Most of these increases dissipated by 22 and 50 days of age. However, at 140 days of age rats of both sexes that had received neonatal phenobarbital showed increased levels of cytochrome P-450, as well as both P-450 and cytochrome c reductase, ethoxycoumarin O-deethylation, glucuronyl transferase activity, in vitro covalent binding of benzo[a]pyrene to DNA and in vivo covalent binding of aflatoxin B1 to hepatic macromolecular fractions. Neonatal phenobarbital administration can alter the metabolic profile of rats in adulthood, apparently by a mechanism different from that responsible for either transitory PB induction or testosterone imprinting.     

Role of 3,5-dichlorophenyl methyl sulfone, a metabolite of m-dichlorobenzene, in the induction of hepatic microsomal drug-metabolizing enzymes by m-dichlorobenzene in rats

The increases in the hepatic microsomal aminopyrine N-demethylase activity and in the content of cytochrome P-450 produced by m-dichlorobenzene (m-DCB) occurred after increases in the hepatic concentration of 3,5-dichlorophenyl methyl sulfone, a minor metabolite. The extent of increases in aminopyrine N-demethylase activity and in the content of cytochrome P-450 at 48 hr after po administration of 200 mg/kg (1.36 mmol/kg) of m-DCB was almost equal to that 72 hr after the ip administration of 25 mumol/kg of the sulfone (Kimura et al., 1983). m-DCB in liver was not detectable at that time, and the concentration of sulfone was 63 to 70% of that 48 to 72 hr after the ip administration of 50 mumol/kg of sulfone. Administration of m-DCB (200 mg/kg) produced a significant reduction in hexobarbital sleeping time, but this reduction was less than that produced by administration of the sulfone (50 mumol/kg). The protein band patterns by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the microsomes from rats treated with the sulfone and m-DCB were similar to those of phenobarbital-treated rats but were different from those of 3-methylcholanthrene-treated rats. The sulfone showed type I interaction with the cytochrome P-450 (Ks, 0.17 mM). The sulfone was formed from the sulfide but reduction of the sulfone was not observed when it was incubated in a hepatic microsomal preparation. The pattern of induction by the sulfone and m-DCB was similar to that by phenobarbital and differed from that by 3-methylcholanthrene. From these results, 3,5-dichlorophenyl methyl sulfone is considered to be a major contributing factor of the inducing activity of m-DCB and to be a potent phenobarbital-like inducer.     

Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants

Electroencephalographic (EEG) effects of 450191-S and its metabolites were investigated in unanesthetized rabbits with chronic electrode implants, and they were compared with those of nitrazepam and estazolam. 450191-S at doses of 0.1-0.5 mg/kg, i.v., induced a drowsy pattern of spontaneous EEG: high voltage slow waves and spindle bursts increased in the cortex and amygdala, while the hippocampal theta rhythm was desynchronized. In addition, low voltage fast waves appeared particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus was markedly suppressed by 450191-S. The photic driving response elicited by a flash light in the visual cortex was significantly suppressed by 450191-S. 450191-S showed no significant effect on the recruiting response. The EEG effects of nitrazepam were qualitatively similar but less potent and shorter in duration of action than those of 450191-S. The effects of estazolam were approximately as potent as those of 450191-S, but its duration of action was much shorter than that of 450191-S. 450191-S was more potent than nitrazepam and approximately equipotent to estazolam in suppressing hippocampal and amygdaloid after-discharges. The EEG effects of M-1 and M-2 were similar to those of 450191-S in both qualitative and quantitative aspects. The effects of M-A were quantitatively similar but less potent and shorter in duration of action than those of 450191-S.     

Pharmacological studies of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivatives (450191-S) (I). Behavioral analysis

The behavioral effects of 450191-S and its metabolites were investigated in mice, rats, cats and rhesus monkeys, and they were compared with those of related benzodiazepines (BDZ) such as diazepam and nitrazepam. Oral administration of 450191-S consistently caused sedation without excitability in mice and rats, and it was only 1/2 to 1/266 as potent as the BDZ in producing motor incoordination as assessed by traction, rotarod performance and inclined screen tests in mice, induced much less ataxia in cats and monkeys, and inhibited respiration in anesthetized cats. The locomotor activities of mice and rats measured by Animex and the open field test were not affected by 450191-S, but rearing and preening decreased with 450191-S as with the BDZ. 450191-S was equipotent with nitrazepam and 2 to 6 times more potent than diazepam and estazolam in potentiating chlorprothixene-induced hypnosis and thiopental-Na-induced anesthesia. These effects were not different with successive 14-day administration of 450191-S. Anti-pentylenetetrazol, picrotoxin and bicuculline convulsions of 450191-S had the same potency as nitrazepam, but caused much less anti-electroshock convulsion than the BDZ. 450191-S had potent antianxiety activity as observed by anti-aggressive and anti-conflict activities and had almost the same effect as diazepam on operant behavior. The metabolites M-1, M-2, M-A and M-3 showed approximately the same potency as 450191-S in inducing anesthetic potentiation and antianxiety activity, but they were much more potent in causing disturbance of the somatic functions. These results indicate that 450191-S possesses inhibitory effects on the central nervous system, including a potent sleep-inducing effect, and is characterized by markedly weak muscle relaxant activity and motor incoordination.     

Induction of hepatic CYP2B1/2 by a teratogenic compound cis-1-[-4-(p-menthane-8-yloxy)phenyl]piperadine (YM9429) in rats

A teratogenic compound cis-1-[-4-(p-menthane-8-yloxy)phenyl]piperadine (YM9429) selectively induces skeletal malformations characterized by cleft palate in rat fetuses. In the present study, we investigated the effect of YM9429 on hepatic cytochrome P-450s and their activities in rats. Oral administrations of YM9429 at a dose of 250, 500 or 750 mg/kg daily for 3 days induced cytochrome P-450 contents in a dose-dependent manner. Concomitant induction of enzyme activities of benzphetamine N-demethylase, erythromycin N-demethylase and, to a lesser extent, aminopyrine N-demethylase was observed. Immunoblot analysis revealed that YM9429 up-regulated hepatic levels of CYP2B1/2 and CYP3A1/2 proteins. A single dose of YM9429 at 250 mg/kg induced CYP2B1/2 protein levels significantly. These results suggest that YM9429 is a strong inducer of cytochrome P-450 with characteristics resembling those of phenobarbital.     

Studies on metabolism and disposition of sizofiran (SPG), an anti-tumor polysaccharide. II. Effects on hepatic drug-metabolizing enzyme system in rats

The effect of a single or multiple administration of sizofiran (SPG), an anti-tumor polysaccharide, on a hepatic drug-metabolizing enzyme system was studied in rats. When SPG was given intravenously at a single dose of 0.5 or 10 mg/kg, no alteration was observed in activities of aminopyrine (AP) N-demethylase and aniline hydroxylase, and in cytochrome P-450 (P-450) content in the livers of rats 48 h after dosing. However, only AP demethylase activity decreased by 34% after the administration of 200 mg/kg. Similarly, no change in the hepatic enzyme activities and P-450 content was observed for up to 180 d after a single dose of 10 mg/kg. Subcutaneous treatment of animals with either 10 or 40 mg/kg dose for 3 and 6 months resulted in no alteration in the enzyme activities and P-450 content. These results may indicate that the therapeutically effective dose of SPG has no effect on a hepatic drug-metabolizing enzyme system in rats.     

Pharmacological studies of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative (450191-S) (V). General pharmacological activities

General pharmacological activities of 450191-S were studied in various species of animals and compared with those of reference benzodiazepines (BDZ). 450191-S at doses of 10 mg/kg slightly decreased (-5 degrees C) the rectal temperature of rabbits. 450191-S decreased respiratory and heart rates in anesthetized cats, but the effects were less than those of diazepam or triazolam. 450191-S increased respiratory and heart rates in conscious dogs, but had no effect on the blood pressure, electrocardiogram and autonomic nervous system in cats and dogs. The drug displayed a slight spasmolytic activity in the small intestine of guinea pigs and a slight inhibitory effect on isolated non-pregnant and pregnant uteri of rats. These effects were less than those of diazepam or nitrazepam. Below doses of 25 mg/kg, 450191-S did not affect urinary volume and electrolyte excretions in rats. It also decreased brain norepinephrine (NE) turnover rates in rats, but decreased NE and dopamine turnover rates in mice. These effects of 450191-S were less than those of nitrazepam. 450191-S was found to be minimally irritating to the ocular mucosa in rabbits and did not irritate the stomach and small intestine in rats. These effects were also compared with those of active metabolites of 450191-S, M-1, M-2, M-A, M-3 and M-4, and the superiority of the mother compound over its metabolites was clarified.     

Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats

The present study examined comparative self-administration of some typical CNS-affecting drugs with a new sleep-inducer, 450191-S, in rats, Most animals self-administered both methamphetamine and cocaine in an extremely stable and invariable fashion with cycles of alternating responding and non-responding periods during the day and at night. Response frequency increased in proportion to a fixed-ratio value. An initial increase in response rate followed by cessation of the responding was observed during extinction. Sixty-five percent of the rats tested self-administered morphine in a relatively variable and less stable fashion. Total daily morphine intake was directly related to the unit dose. Eighty-three percent of the rats self-administered pentazocine. Fifty and sixty-four percent of the rats maintained self-administration of phenobarbital and diazepam, respectively, with higher intake at night than during the day. Responding persisted at a low rate for several days during extinction. Abrupt withdrawal of 450191-S caused the same slight weight loss and moderate decrease in food intake as those seen with diazepam and nitrazepam, and cross-physical dependence between 450191-S and diazepam was found. Self-administration of 450191-S at 0.5-2.5 mg/kg/infusion was observed with 2 out of 11 rats, which was much less than that found with diazepam. These results suggest that 450191-S possesses little, if any, drug dependence liability of the tranquilizer type.     

Induction of hepatic mono-oxygenase systems of pregnant rats with phenobarbital and 3-methylcholanthrene.

When sodium phenobarbital was given to pregnant and non-pregnant female rats (40 mg/kg for 4 days), ethylmorphine N-demethylase, a cytochrome P-450-dependent system, was induced about 4-fold in non-pregnant females, but only 2-fold in pregnant females. The induction of microsomal cytochrome P-450 was also lower in pregnant animals. This impairment of phenobarbital induction occurred within 3 days of conception and disappeared after parturition within 5 days. 3-Methylcholan-threne induction of hepatic benzo[a]pyrene hydroxylase, a cytochrome P₁-450-dependent mono-oxy-genase system not inducible by phenobarbital, was not impaired during pregnancy. The depressed response of the maternal liver to phenobarbital induction can be partially reversed by the coadministra-tion of 3-methylcholanthrene. The administration of a higher dose of sodium phenobarbital (80 mg/kg day for 4 days) overcame the pregnancy-related lowered response to phenobarbital induction observed with the smaller dose of the barbiturate. The similarity in responses of the maternal and fetal livers to inducing agents suggests that a common regulatory mechanism operates in both the fetus and the pregnant female.     

Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[a]pyrene treatment in rats

Simultaneous administration of caffeine (100 mg/kg, i.p., 3 days) and phenobarbital (80 mg/kg, i.p., 3 days) to adult male rats resulted in a significant decrease in hepatic cytochrome P-450 and acetanilide hydroxylase activity, compared to phenobarbital administration alone. While simultaneous administration of caffeine and benzo[a]pyrene (20 mg/kg, i.p., 2 days) increased acetanilide hydroxylase, compared to benzo[a]pyrene administration, no change was seen in the cytochrome P-450 concentration. In vitro addition of 2.5 mM caffeine to microsomal incubations from untreated, phenobarbital- and benzo[a]pyrene-treated rats inhibited aminopyrine N-demethylase activity. No significant difference was seen in the extent of aminopyrine N-demethylase inhibition due to the in vitro addition of caffeine to microsomes from untreated or phenobarbital-treated rats, whereas inhibition in microsomes from benzo[a]pyrene-treated rats was greater.     

Interactions between theophylline and drug metabolizing liver enzymes in the rat

Theophylline induces increase of hepatic cytochrome P-450 contents and P-450 dependent polysubstrate monooxygenases (e.g. p-nitroanisol-demethylase, 7-ethoxycoumarin-deethylase) in rats and other animals and in man. The purpose of this study is to investigate the long-term effect of theophylline on hepatic cytochrome P-450 and P-450 dependent enzyme activities in rats. P-450 content is enhanced after 6 days treatment with theophylline (150 mg/kg/d orally), but reaches the initial level after 28 days treatment. However, the P-450 dependent enzyme activities (7-ethoxycoumarin-deethylase, p-nitroanisol-demethylase) remain elevated. The in vitro inhibition of 7-ethoxycoumarin-deethylase by alpha-naphthoflavone and metyrapone suggests a mixed type induction by theophylline. Treatment of the animals with phenobarbital and theophylline or with benzo(alpha)pyrene and theophylline does not lead to an enhancement of P-450 content compared with a treatment solely by phenobarbital or benzo(alpha)pyrene. However, the simultaneous application of theophylline and phenobarbital increases the 7-ethoxycoumarin-deethylase and p-nitroanisol-demethylase activities compared with an exclusive phenobarbital treatment, whereas the benzo(alpha)pyrene effect is not enhanced by theophylline.     

Induction of rat cytochrome P-450 3 and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl

Rat cytochrome P-450 3 (P-450 3) is a constitutive hepatic steroid hormone 7 alpha-hydroxylase which is relatively unresponsive to a number of monooxygenase-inducing agents. The present study demonstrates that a polyhalogenated aromatic hydrocarbon inducer, 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), induces P-450 3 in livers of adult male rats, and that the increase is the result of an increase in the mRNA for this enzyme. Cytochrome P-450 3 and its mRNA were increased more slowly and to a lesser extent than cytochrome P-450c (P-450c) and its mRNA, indicating that these enzymes are not regulated coordinately in liver. The maximum increase in P-450 3 and P-450 3-dependent androstenedione 7 alpha-hydroxylase activity (2- to 3-fold) occurred 7 days after administration of HCB, in contrast to the increase in P-450c (greater than 200-fold) which was maximal by 3-5 days. The rate of induction of P-450 3 mRNA was also slower [maximum increase (9-fold) at 5 days after HCB administration] than that of P-450c mRNA [maximum increase (30-fold) at 2-3 days]. Moreover, a higher dose of HCB was required to produce maximum induction of P-450 3 (50 mg/kg) than that required to produce maximum induction of P-450c (10 mg/kg). P-450 3 was not detected on Western blots of lung, kidney, or prostate microsomes isolated from control or HCB-treated rats (less than or equal to 2% of that found in livers of HCB-treated rats). Moreover, P-450 3-dependent steroid 7 alpha-hydroxylase activity was not detected in these extrahepatic tissues of control or HCB-treated rats (less than or equal to 1% of that found in the corresponding liver microsomes of untreated or HCB-treated rats). In contrast, P-450c was increased dramatically by HCB in lung, kidney, and prostate tissues, indicating differential expression of P-450c and P-450 3 in extrahepatic tissues.     

The effect of pretreatment with dieldrin on certain in vivo parameters of enzyme induction in mice

The present investigation was undertaken in order to study under which conditions certain in vivo parameters (LD50, sleeping time, and tissue concentrations of a given drug) would best characterize the phenomenon of enzyme induction in mice pretreated with the organohalogenated insecticide dieldrin. Five barbiturates (barbital, hexobarbital, pentobarbital, thiopental and phenobarbital) possessing different metabolic pathways were selected as the test drugs, and the influence of the route of administration (iv, ip, sc and po) upon their ultimate pharmacologic effect was evaluated.The results obtained show that dieldrin given at a dose of 25 mg/kg/day sc for 5 days, is a liver microsomal enzyme inducer based on its effect on the amount of cytochrome P-450 and the enzymatic activity of 9000 g supernatant preparations with various barbiturates used as substrates. Dieldrin significantly increased the LD50 values of phenobarbital, regardless of the route of administration. Dieldrin also raised the LD50 of hexobarbital, thiopental and pentobarbital administered by all but the iv route; however, it did not modify the LD50 of barbital. The inducer was effective in significantly reducing the duration of sleep with hexobarbital, thiopental, pentobarbital and phenobarbital via all routes of administration. The sleeping time with barbital was significantly reduced when it was given by the po route; however, it was found that dieldrin-treated mice awoke with brain concentrations of barbital that were significantly higher than those in the control animals. Dieldrin was effective in reducing the concentrations of hexobarbital in the blood and brain following all routes of administration. The same was true for pentobarbital, except in blood after an iv injection.Under suitable experimental conditions, therefore, results of tests performed in intact animals correlate well with microsomal enzyme assays, thus reinforcing evidence for enzyme induction. However, the administration of an inducer, like dieldrin, could lead to “satellite” phenomena unrelated to microsomal enzyme induction.     

Effect of phenobarbital induction on galactose elimination capacity in the rat

The capacity to eliminate galactose is used clinically and experimentally as a quantitative test of liver function. Patients with liver disorders often receive drugs which induce changes in hepatic enzymes, and therefore the influence of such drugs on the galactose elimination capacity in rats was investigated.A paired experiment was performed with 11 pairs of female Wistar rats weighing about 200 g. Each pair received daily intraperitoneal injections of either phenobarbital (50 mg/kg) or isotonic saline for 8 days. The galactose elimination capacity was estimated by intravenous infusion of galactose.Phenobarbital increased significantly the weight of the liver, the lactate dehydrogenase activity, the microsomal protein, and the hepatic content of cytochrome P-450. The galactose elimination capacity was not significantly changed by phenobarbital and was related neither to the total content of cytochrome P-450 nor to the total lactate dehydrogenase activity.It is concluded that galactose elimination in rats is independent of enzyme induction by phenobarbital.     

Regulation of renal cytochrome P-450. Effects of two-thirds hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes

The possibility of a relationship between hepatic and renal cytochrome P-450 contents was assessed in rats with liver disease. In rats killed 3 days after two-thirds hepatectomy (a model for hepatocellular insufficiency), the total microsomal cytochrome P-450 content of the whole liver was decreased by 60% as compared to that in control rats; renal cytochrome P-450 was increased by 30% while the 7-ethoxycoumarin deethylase activity of kidney microsomes was increased by 80%. In rats killed 7 days after bile duct ligation (a model for cholestasis) or 35 days after bile duct ligation (a model for biliary cirrhosis), hepatic cytochrome P-450 was decreased by 60% and 45%, respectively, while renal cytochrome P-450 content was increased by 50% and 150%, respectively. In contrast, in rats killed 15 days after the last dose of carbon tetrachloride, 1.3 ml/kg twice weekly for 3 months (a model for post-necrotic cirrhosis), both hepatic and renal cytochrome P-450 contents remained unchanged. Phenobarbital (80 mg/kg daily for 3 days) was a poor inducer of renal cytochrome P-450 in sham-operated rats but became a potent inducer of renal cytochrome P-450 in rats with two-thirds hepatectomy. We conclude that renal cytochrome P-450 is increased in three models in which hepatic cytochrome P-450 contents are decreased (two-thirds hepatectomy, cholestasis and biliary cirrhosis), but remains unchanged in a model of severe liver pathology, in which hepatic cytochrome P-450 content is not modified (late, post-necrotic cirrhosis). The hypothetical role of endogenous inducer(s) is discussed.     

Effect of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative, on cerebral content of neuroactive amino acids

The effect of 450191-S, one of the 1H-1,2,4-triazolyl benzophenone derivatives and possessing benzodiazepine-like anti-anxiety actions, on the content of various amino acids in the mouse brain was examined in comparison with that of nitrazepam. Among the various amino acids examined, only glycine, aspartic acid and alanine showed a statistically significant decrease following the oral administration of 450191-S. The oral administration of nitrazepam also induced a similar decline in the cerebral contents of glycine and alanine. Furthermore, it was found that the administration of Ro 15-1788, a benzodiazepine antagonist, eliminated the 450191-S-induced decline in the cerebral contents of glycine and aspartic acid. These results indicate that the administration of 450191-S induces the decrease of glycine and aspartic acid, neuroactive amino acids, in the brain, possibly via the activation of benzodiazepine receptors.