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Metabolism of Drugs in Old Rats (Ii) Metabolism in Vivo and Effect of Drugs in Old Rats

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Metabolism of Drugs in Old Rats (Ii) Metabolism in Vivo and Effect of Drugs in Old Rats METABOLISM OF DRUGS IN OLD RATS (II) METABOLISM IN VIVO AND EFFECT OF DRUGS IN OLD RATS RYUICHI KATO AND AKIRA TAKANAKA Department of Pharmacology, National Institute of Hygienic Sciences, Setagaya-ku, Tokyo Received for publication March 16, 1968 It is well known that the effects of some drugs in old animals quite differ from those in young animals. For example, Farner and Verzar (1) observed that the action of am phetamine to increase moter activity was more marked in young rats than in old rats and the action of hexobarbital to antagonized against the amphetamine action was more ef fective in old rats than in young rats. Moreover, the duration of hexobarbital anesthesia was longer in old rats than in young rats (2). Similarly, Petty and Karler (3) observed that anticonvulsive activity of acetazolamide and phenobarbital was more marked in old rats than in young rats. However, there is no study on the mechanism of such altered drug response in rela tion to the rate of drug metabolism. In a previous paper it was reported from our labo ratory that the activities in the oxidation and reduction of drugs and NADPH-linked elec tron transport system in liver microsomes of male and female rats were progressively decreased with aging (4). It is, therefore, of interest to investigate whether or not the metabolism in vivoof vari ous drugs is decreased in old rats in accordance with the decrease in the metabolic activi ties of liver microsomes observed in the in vitro experiments. Moreover, the relationship between the effects of drugs and the rate of in vivo metabolism of drugs in the old rats was studied. MATERIALSAND METHODS Male and female rats of Wistar strain of about 40, 100, 300 and 600 days old were used . In most of experiments, 100 days old rats (young rats) and 600 days old rats (old rats) were used. Pentobarbital sodium, hexobarbital sodium, strychnine sulphate and OMPA (octa methylpyrophosphoramide) were dissolved in distilled water and carisoprodol was sus pended with 1 % solution of sodium carboxymethylcellulose and all drugs were given intraperitoneally. The preparation of microsomes and the determinations of pentobarbital and cariso prodol oxidation were carried out according to the methods described in a previous paper (4). The metabolism in vivo of carisoprodol and pentobarbital were determined by the rate of disappearance of the drugs in the serum and brain after intraperitoneal injection . 力rl月暴1籔 … ・ド石イ中 正 The determinations of carisoprodol and pentobarbital were carried out according to the method of Kato et al. (5) and Brodie et al. (6). Carisoprodol and zoxazolamine paralysis and pentobarbital narcosis were determined by the duration of loss of the righting reflex. The toxicity of strychnine was evaluated by the convulsion and mortality. The toxicity of OMPA was evaluated by the time required for the onset of the toxic symptoms, convulsion and mortality in 50% of the treated rats. TABLE 1. Metabolism in vitro and in vivo of carisoprodol in young and old male rats. RESULTS 1. Metabolism of carisoprodolin young and old rats Table 1 shows that the metabolism of carisoprodol by liver microsomes of the old male rats is markedly slower than in the young. Since the ratio of liver weight per 100 g body weight is demonstrated to be smaller in the old rats than in the young (4), the age difference is more evident in the activity of carisoprodol oxidase per 100 g body weight. The rate of decrease in the concentration of carisoprodol in the brain and serum in young and old male rats is given in Fig. 1. Since the rate of decrease in the concentration of carisoprodol was mainely regulated by the rate of metabolism Fir. 1. The rate of metabolism in vivo of cariso prodol in young and old male rats. in vivo, these results indicated that the rate Carisoprodol (200mg/kg) was given in of metabolism in vivo of carisoprodol was traperitoneally. The rats were killed 30, 60. 120, 180 and 300 minutes after the slower in the old rats than in the young. administration and the serum (lower) and The biological half-life of carisoprodol in brain (upper) concentrations of cariso prodol were determined. The each value the young male rats was 97 minutes, while is average of 5 rats. TABLE 2. Metabolism in vitro and in vivo of carisoprodol in young and old female rats. that in the old male rats was 199 minutes. Thus, the difference between the young and old rats in the activity of carisoprodol oxidase per 100 g body weight was similar to that in the rate of in vivo metabolism. Moreover, the metabolism of carisopro dol by liver microsomes in female rats was slower in old rats than in the young (Table 2). The rate of metabolism in vivoof cariso prodol in the young and old female rats is given in Fig. 2. The rate of metabolism in vivo of carisoprodol was faster in the young female rats than in the old female. 2. Metabolism of pentobarbital in young and old rats The rate of metabolism in vivo of pento barbital was slower in the old male rats than in the young male (Table 3). The difference between the young and old rats FIG. 2. The rate of metabolism in vivo of cariso prodol in young and old female rats. See the legend for Fig. 1. TABLE 3. Metabolism in vitro and in vivo of pentobarbital in young and old male rats. TABLE 4. Metabolism in vitro and in vivo of pentobarbital in young and old female rats TABLE 5. Duration of pentobarbital narcosis in young and old rats. in the rate of metabolism in vivo of pentobarbital was similar to that in the activity of liver pentobarbital oxidase per 100 g body weight. Similarly, the metabolism in vitro and in vivo of pentobarbital was slower in the old female rats than in the young female (Table 4). 3. Duration of pentobarbital narcosis in young and old rats The duration of pentobarbital narcosis was longer in the old male rats than in the young male (Table 5). Similarly, a long duration of pentobarbital narcosis was observed in the old female rats than in the young, but the difference in the duration of pentobarbital narcosis between the young and old rats is more marked in the male rats than in the female. The difference in the duration of pentobarbital narcosis of the old male rats is 297% of the young rats, while in the female the difference is 93%. The discrepancy between the rate of in vivo metabolism and the duration of pentobarbital narcosis is probably due to the dose of pen tobarbital employed in the present investigation, and a small difference in the rate of the metabolism between the male and female rats may be exaggerated in the duration of action. Moreover, there was no clear difference in the brain concentration of pentobarbital on awaking. These results suggest that the difference in the duration of pentobarbital narcosis is likely not only due to the difference in the sensitivity of the central nervous system to the drug, but it is rather due to the decreased rate of the drug metabolism in the old rats (7-10). 4. Duration of carisoprodil and zoxazolamineparalysis in young and old rats The duration of carisoprodol paralysis was longer in the old male rats than in the young male (Table 6). Similarly, the duration of carisoprodol paralysis was longer in the young female rats than in the old female, but the percentage of the prolongation in the duration of carisopro dol paralysis in the old rats is somewhat greater in the male rats than in the female . The duration of zoxazolamine paralysis was longer in the old male rats than in the young male (Table 7). In contrast to the duration of pentobarbital narcosis and cariso prodol paralysis, there was no clear sex difference in the duration of zoxazolamine paraly sis and the percentage prolongation in the zoxazolamine paralysis was almost same in the old male and female rats. TABLE 6. Duration of carisoprodol paralysis in TABLE 7. Duration of zoxazolamine paralysis young and old rats. in young and old rats. TABLE 8. Toxicity of strychnine in young and old rats. 5. Toxicity of strychnineand OMPA in young and old rats The toxicity of strychnine was higher in the old male rats than in the young male (Table 8). Similarly, the toxicity of strychnine was higher in the old female rats than in the young female, but the increase in the toxicity of strychnine in the old rats was somewhat greater in the male rats than in the female. In contrast, the toxicity of OMPA (octamethylpyrophosphoramide) was lower in the old male rats than in the young male (Table 9). The mortality of the young rats caused by 5 mg/kg and 10 mg/kg of OMPA was 40% and 100%, respectively, while killed none TABLE 9. Toxicity of OMPA in young and old male rats. of the old rats by the administration of 10 mg/kg. These results are due to the fact that the anti-cholinesterase activity of OMPA is due to an active metabolite (hydroxylated OMPA) and the toxicity of OMPA is closely related to the activity of liver microsomal enzyme which activates OMPA (11, 12). 6. Effect of phenobarbital treatmenton the duration of hexobarbitalnarcosis in differentaged female rats In previous papers it was observed that the effects of phenobarbital to increase in the activities of microsomal drug-metabolizing enzymes and NADPH-electron transport system were decreased with the increase in age and in the old rats significant increase of the ac tivities by phenobarbital was not observed any more (13, 14).
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