Effect of P-glycoprotein inhibitor (Carvedilol) on pharmacological and hematological effects of its substrate (methotrexate) on pregnant and lactating rat mothers

Abstract

Sixty albino rats (40 female rats and 20 males) were allocated into four dosing groups administered orally carvedilol (T1) 0.72mg/kg, methotrexate (T2) 0.36mg/kg, combined doses (T3) carvedilol + methotrexate and control group (Distilled water) for 2 months in male and 2 weeks in female rats before mating and after copulation and approval of pregnancy, dosing continued in female groups during pregnancy and lactation periods. Half of the animal groups were euthanized one day before parturation to determine P-gp concentration in the placenta and liver of pregnant mothers. In contrast, the other half was left for parturition and lactation to study the effects of carvedilol (P-gp inhibitor) on methotrexate (P-gp substrate) when given alone and in combination with some pharmacological, hematological, and biochemical parameters in lactating mothers and pups at the end of lactation. The pharmacological results showed the highest significant antinociceptive responses both in the early and late phase in the T3 (CV+MTX) followed by the T2 (MTX) group. In contrast, the T1 (Cv) animal group showed nearly resembling results as that of the control group in the early and late phases of the formalin test. The written test also recorded the same result as the Formlin test, indicating a significantly higher analgesic effect in T3 followed by T2 in comparison to T1 and control groups. The TNF alpha results supported the anti-inflammatory effect, recording a significant decline mainly in the T3 and T2 groups. The hematological results recorded significantly more reduction in WBC levels in mother and their pups in comparison with T1 and control groups. The serum electrolyte levels (Na+, K+, Ca+2) recorded in all treated groups and pups showed a significant increase in potassium levels in the T1 and T2 mother rat groups. The P-glycoprotein (P-gp) concentration measured in liver and placenta of euthanized pregnant mother before delivery recorded potent inhibition of P-gp in T1 & T3 groups which might altered pharmacokinetic and pharmacodynamic effects of substrate by carvedilol that considered a potent P-gp inhibitor drugs, this might explain our results of increase in pharmacological effect of methotrexate and their side effect on electrolyte concentration and hematology in combined group of CV+ MTX. Keywords: Carvedilol, Methotrexate, p-gp inhibitor, Anti-inflammatory, Hematology, Electrolyte.