Characterisation of cytochrome P450 isoenzyme activity in sheep liver and placental microsomes.

INTRODUCTION: Drug metabolism during pregnancy is a complex process that involves maternal, placental and fetal sites of metabolism. Indeed, there is a lack of clarity provided from drug metabolism in human pregnancy due to ethical limitations. Large animal models of human pregnancy provide an opportunity to quantify activity of phase 1 drug metabolism mediated by cytochrome P450 (CYP) enzymes in the maternal, placental, and fetal compartments. Herein, we have validated a comprehensive assay to quantify maternal, placental, and fetal CYP activity. METHODS: Isolated microsomes from sheep maternal liver, placenta, and fetal liver (140d gestation, term = 150d) were incubated with CYP-specific probe drugs to quantify the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Inhibition studies were performed to validate specificity of probe drugs. The validated assay was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1 and CYP3A were active in maternal liver. In contrast, only CYP1A2, CYP2C8 and CYP2D6 were active in the placenta, whereas CYP2B6, CYP2C8 and CYP2D6 were active in the fetal liver. Of the placental-specific CYPs validated, CYP1A2 increased in type A compared with type D placentomes, whereas CYP2C8 activity increased in type B compared with type A and C. DISCUSSION: This study has established conditions for compartment-specific CYP activity in the sheep maternal-placental-fetal unit using a validated and standardised experimental workflow. Compartment- and placentome type-specific CYP activity are important considerations when examining drug metabolism in the maternal-placental-fetal unit and in determining the impact of pregnancy complications.

Aspectos farmacocinéticos a tomar en cuenta durante la prescripción de fármacos en el embarazo / Pharmacokinetics aspects to take into account the prescription drug during pregnancy

El embarazo es un estado dinámico durante el cual se presentan diversos cambios considerados como fisiológicos.Un alto porcentaje de mujeres utiliza fármacos durante su embarazo, ya sea este un tratamiento crónico o agudo, por lo que resulta de vital importancia conocer los aspectos farmacocinéticos que podrían tener lugar en el cuerpo debido a los cambios anteriormente mencionados. Un dato esencial a tomar en cuenta y único del estado grávido es la existencia de la unidad feto-placentaria, la cual representa un compartimento aparte con un comportamiento farmacocinético distinto. A continuación se presentará una revisión de los principales cambios farmacocinéticas durante el embarazo que se conocen en la actualidad, lo que nos permitirá mantener un juicio más crítico ante la prescripción de medicamentos en la mujer embarazada.

Pregnancy is a dynamic state during which many changes considered as physiological take place. A high percentage of women use some kind of medication during pregnancy, whether it is chronic or acute treatment, so it is vital to know the pharmacokinetic aspects that could take place in the body due to the changes previously mentioned.An essential fact to consider and unique of the gravid state is the existence of the placental-fetal unit, which represents a separate compartment with a different pharmacokinetic behavior. Below, there is a review of the main pharmacokinetic changes during pregnancy that are known until now, which will allow us to maintain a more critical judgement before prescribing drugs in pregnant women.