An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA-302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 µmol·l-1 ). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.
Effects of early neonatal interventions on metabolic parameters later in life (s.c. late effects) were studied in rats using two models; namely, (a) the effects of premature weaning and (b) the effects of "dietary" manipulations during the suckling period (s.c. small vs. large litters), (a) Premature weaning of rats caused an earlier degeneration of spermiogenesis and elevated plasma cholesterol levels in adult animals when compared to levels found in animals weaned 12 days later (on day 30 after birth). In adult rats, radioiodine uptake in thyroid glands was lower in the group weaned prematurely. Premature weaning was followed by a decrease of corticosterone production in adrenal glands in adult animals; in female adult prematurely weaned rats, an elevated response of adrenal cortex to stressors was observed. Several other studies explored the "immediate" effects of early, premature weaning, (b) Early exposure to high fat diet evoked a hypercholesterolaemic response in adulthood following brief exposure to HF diet. Rats from litters reduced to 3 or 4 pups per mother on postnatal day 3 exhibited 2 days later plasma levels of cholesterol higher than in rats raised in large litters of 8 or 14. The difference between small and large litters was preserved for the whole lifespan of the animals. In adulthood, rats from small litters were fatter and had higher levels of plasma cholesterol and insulin. Other studies suggester that early dietary experience may regulate the pattern of drug metabolism in adult life. An inhibition of diurnal plasma corticosterone variation was found in rats overfed during the neonatal period and an increased stimulation of lipolysis by norepinephrine and lipogenesis by insulin was demonstrated in neonatally underfed rats. Interesting studies were reported in longitudinally studies in children: at the age of 9-12 year brest-fed children (for more than 6 months) had the highest cholesterol levels; on the other hand significantly increased levels of APO B, Apo Al, ATH index and Apo/B Apo A1 quotient (p<0.05) were found in the nonbreast-fed group (27 references).
Adenine-induced model of chronic kidney disease (CKD) is a widely used model especially in studies testing novel nephroprotective agents. We investigated the effects of adenineinduced CKD in rats on the activities of some xenobiotic metabolizing enzymes in liver and kidneys, and on some in vivo indicators of drug metabolism (viz pentobarbitone sleeping time, and plasma concentration of theophylline 90 min post administration). CKD was induced by orally feeding adenine (0.25 % w/w) for 35 days. Adenine induced all the characteristics of CKD, which was confirmed by biochemical and histological findings. Glutathione concentration and activities of some enzymes involved in its metabolism were reduced in kidneys and livers of rats with CKD. Renal CYP450 1A1 activity was significantly inhibited by adenine, but other measured isoenzymes (1A2, 3A4 and 2E1) were not significantly affected. Adenine significantly prolonged pentobarbitone-sleeping time and increased plasma theophylline concentration 90 min post administration. Adenine also induced a moderate degree of hepatic damages as indicated histologically and by significant elevations in some plasma enzymes. The results suggest that adenine-induced CKD is associated with significant in vivo inhibitory activities on some drug-metabolizing enzymes, with most of the effect on the kidneys rather than the liver., M. Al Za’abi, A. Shalaby, P. Manoj, B. H. Ali., and Obsahuje bibliografii