Clearance

Clearance can be subdivided into the two main routes, renal (CL_R) and hepatic (CL_H) clearance as follows:

Many changes occur in the urinary and hepatic system during pregnancy, including an increase in GFR, enhanced creatinine clearance (CL_CR) and hepatic blood flow (Q_H,blood). Also, variable changes in activities of drug-metabolizing enzymes have been reported. Since all four studied drugs are at least partially eliminated by glomerular filtration and only the unbound drug fraction is eliminated, the change in renal clearance during pregnancy was defined by Eq. (6), in which GFR was described by Eq. (7) and CL_R(EGA = 0) is the reported renal clearance in non-pregnant patients.

Limited and contradictory data are reported on the change in Q_H,blood during pregnancy, we therefore assumed that the hepatic blood flow remained unchanged over pregnancy and was thus fixed to a typical non-pregnant value of 109 L/h [11]. Both changes in unbound fraction and changes in Q_H,plasma which change during pregnancy can influence CL_H. A decrease in haematocrit (HCT) is observed during pregnancy, which is described by Eq. (8):

Subsequently, the hepatic plasma flow (Q_H,plasma) can be described with Eq. (9):

To describe the relationship between CL_H, the changing fraction unbound, the hepatic plasma flow (Q_H,plasma) and intrinsic clearance (CL_int), the following well-stirred liver model equation was used:

Equation (10) was rearranged to determine the CL_int in non-pregnant patients, using previously estimated drug-specific values of CL_H (Eq. 11).

To account for the changes in activities of enzymatic pathways during pregnancy, CL_int was corrected for the change in enzyme activity (E):

where E(EGA) represents the enzyme activities of relevant enzymes during pregnancy, and EGA = 0 is the enzyme activity in the non-pregnant state (i.e. 100%). The change in drug-metabolizing enzyme activity of CYP3A4 was described as follows:

Although the activity of CYP2C8 and UGT2B7 might be increased during pregnancy, little is known about the magnitude of this increase [3]. We therefore assumed that the activity of these enzymes remained unchanged over pregnancy.