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1. We have examined changes in caffeine and trimethadione (TMO) metabolism in vivo , agents which are used as probe drugs. In this study the total body clearance ( Cl ) of caffeine and TMO was low 1 week after birth (week 1), increased rapidly from week 3, peaked andthen decreased gradually until reaching the level for themature,adult dog.The elimination half-life ( t ) of caffeine and TMO was prolonged during week 1; however, it then gradually became shorter. Gradually it became longer and reached the level for the adult dog. The apparent volume of distribution ( V ) of caffeine did not change throughout d the study. However, the V of TMO was only high during week 1. d 2. The in vitro changes in a variety of typical substrates for seven different cytochrome P450 (CYP) isozymes were examined. In this study three different patterns of metabolism can be identified: (1) activity is low immediately after birth, increases, peaks and then decreases to the adult dog level ( p -nitroanisole; CYP1A1, caffeine; CYP1A2, benzphetamine; CYP3A 2B(?), aniline; 2E1 and TMO; CYP2C9 2E1 3A4); (2) activity generally increases rapidly soon after birth, continues to increase,peaks and then gradually decreases to the adult level (phenytoin; CYP2C9); and (3) activity is high (about the same level as the adult) immediately after birth, decreases and then gradually increases to the adult level (erythromycin; CYP3A4 5). 3. The results of these in vivo and in vitro studies suggest that changes in enzyme activity are due to differences in P450 isoenzymes during development. [ABSTRACT FROM AUTHOR]

1. After oral administration of C-labelled (5 R )-3-\[2-((1 S )-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone (E2011) at a dose of 1 mg kg, the blood level of radioactivity reached a maximum concentration ( C ) of max 0 545 mu g eq. ml after 0 25 h in the rat and of 0 900 mu g eq. ml after 0 5 h in the dog. In dog plasma, C for radioactivity and unchanged E2011 were 0 862 mu g eq. ml and 0 650 mu g ml max respectively with corresponding T (time at C ) of 0 75 and 0 25 h. The unchanged max max drug in dog plasma was below the detection limit (5 ng ml plasma) after 24 h. 2. The tissue levels of radioactivity were measured at 0 25 ( T ), 6, 24, and 168 h after max administration to the rat and at 0 5 ( T ), 24, and 168 h in the dog. The radioactivity was max distributed in all tissues examined at T in the rat and dog. The radioactivity levels of the max cerebral cortex in the rat and dog were 26 and 36% of the plasma level at T . The max radioactivity in tissues decreased at almost the same rate as that in plasma. Plasma protein binding of the unchanged drug in the rat in vitro were about 70% in the range of 0 1-10 mu g ml, and those in the dog were about 45% in the same concentration range. 3. Cumulative excretion of radioactivity in the rat was 74 5% in urine and 22 5% in faeces after 7 days. In the dog, 55 5 and 36 5% of the radioactivity administered were excreted in urine and faeces respectively after 7 days. The biliary excretion of radioactivity in the cannulated rat was 23 0% within 48 h. 4. In tlc analysis of plasma and tissues of the rat and dog, the radioactivity for the unchanged drug was much higher than metabolites. In tlc analysis of urine, the same metabolites were detected in the rat and dog, and the radioactivity of a metabolite, IM1, was the highest in the both animals. Eight metabolites were detected in the plasma, tissues and excreta of the rat, and four metabolites in the dog. 5. In conclusion, the absorption, distribution, metabolism and excretion of Clabelled E2011 in the rat and dog have been established, and only minor differences were observed between these species. [ABSTRACT FROM AUTHOR]