Effects of pregnancy and lactation on warfarin-induced changes in blood coagulation-related parameters in rats.

Effects of pregnancy and lactation on warfarin-induced changes in blood coagulation-related parameters were examined in rats. Warfarin (0.5 mg/kg/day) was given orally to pregnant and non-pregnant rats for 3 days from gestation day (GD) 17 to 19 or to lactating and non-pregnant rats for 3 days from post partum day (PPD) 10 to 12. Blood samples were collected from the rats on the day following the last administration (GD 20 or PPD 13) to measure prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombotest (TBT), factor VII and X activities and anti-thrombin III concentration (ATIII). Administration of warfarin to non-pregnant rats resulted in significant prolongation of APTT and TBT and significant decreases in factor VII and X activities. On the other hand, similar but not significant changes were observed in pregnant rats and similar significant but less prominent changes were observed in lactating rats. The reduction of the anticoagulant effects of warfarin may partially be related to high plasma 17beta-estradiol concentration in pregnant rats and to high plasma prolactin concentration in lactating rats, respectively.

Phenobarbital (PB)-induced changes in blood coagulationrelated parameters in pregnant rats, lactating rats and pups.

Effects of repeated administration of phenobarbital (PB) on blood coagulation-related parameters were examined in non-pregnant, pregnant and lactating rats, and also in pups born to PB-treated lactating dams. PB was orally administered at a dose level of 80 mg/kg/day to pregnant (from gestation day (GD) 13), postpartum (from postpartum day (PPD) 7) and non-pregnant rats (from 13 weeks of age) for 7 days. Blood was collected on GD20 or PPD14 to perform blood coagulation examination. Concurrently, the blood coagulation parameters were examined in the pups. Increases in liver weight and/or hepatic cytochrome P450 content were observed in the PB-treated non-pregnant, pregnant and lactating rats. Activated partial thromboplastin time (APTT) was prolonged and anti-thrombin III (ATIII) concentration was increased in the lactating rats, while there were no changes in prothrombin time (PT) or APTT in the non-pregnant and pregnant rats. Moreover, prolongation of PT and APTT and decreases in factors VII and IX activities were observed in their pups. Thus, prolongation of blood coagulation time was confirmed in both dams and their pups following PB-administration to lactating dams. Effects of vitamin K(2) (VK(2)) on PB-induced changes in blood coagulation-related parameters of both dams and their pups were examined by co-administration with PB and VK(2) to lactating dams. PT and APTT were comparable to the control and PB-induced prolongation of blood coagulation time was improved in the pups while APTT was prolonged in dams, suggesting that VK(2) was beneficial to pups but not to dams.

Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats.

Carbon tetrachloride (CCl4) is well known to induce hepatotoxicity after being metabolized to trichloromethyl free radical ((.)CCl3) by CYP2E1. In the present study, the hepatotoxicity induced by a single oral dose (2,000 mg/kg) of CCl4 was compared between pregnant (gestation days (GD) 13 and 19) or postpartum (postpartum days (PPD) 1, 13 and 27) and non-pregnant rats. Hepatotoxicity in CCl4-treated pregnant rats evaluated by blood chemistry (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities) and histopathological finding (area of damaged hepatocytes) was minimal on GD19, being weaker than that in non-pregnant rats. CYP2E1 expression in non-treated pregnant rats decreased as pregnancy progressed and reached minimum level on GD19. Thus, the degree of CCl4-induced hepatotoxicity roughly corresponded to CYP2E1 levels during pregnancy. After delivery, hepatotoxicity in CCl4-treated lactating rats was maximal on PPD13, being stronger than that in non-pregnant rats, and then it decreased slightly on PPD27. The CYP2E1 level in the non-treated lactating rats tended to increase but remained at lower levels until PPD13 compared with that in non-pregnant rats. Thus, the degree of CCl4-induced hepatotoxicity did not correspond to CYP2E1 levels during lactation. This suggests that during lactation, there may be certain factors other than CYP2E1 expression responsible for the degree of CCl4-induced hepatotoxicity.

Blood coagulation-related parameter changes in Sprague-Dawley (SD) rats treated with phenobarbital (PB) and PB plus vitamin K.

Effects of dose and duration of phenobarbital (PB) administration and those of co-administration of PB and vitamin K on blood coagulation-related parameters were examined in specific pathogen-free (SPF) rats of Sprague-Dawley strain kept on an ordinary diet. In Experiment 1, oral administration of PB (0, 25, 50, 100 or 150 mg/kg/day) for 2 weeks induced increases in hepatic cytochrome P450 content and CYP2B expression, prolongation of coagulation time (activated partial thromboplastin time (APTT) and Thrombotest (TBT)) and an increase in anti-thrombin III (AT III) concentration in a dose-dependent manner. In Experiment 2, PB administration (100 mg/kg/day) for up to 14 days produced time-dependent increases in hepatic cytochrome P450 content and CYP2B (CYP2B1 and CYP2B2) expression. APTT was prolonged from day 1 and AT III concentration was increased from day 2, whereas the coagulation time (TBT) was prolonged from day 7. In Experiment 3, APTT prolonged by PB (100 mg/kg/day) was shortened after vitamin K(2) (30 mg/kg/day) co-administration, although AT III concentration was still increased. This suggests that not AT III but PB-induced vitamin K deficiency may play an important role in PB-induced prolongation of coagulation time in SPF rats kept on an ordinary diet.