Effect of pregnancy on the pharmacokinetics of acetaminophen in rats

Acetaminophen (A), in single doses of 15 mg/kg and 300 mg/kg, was administered by i.v. injection to nonpregnant (180-240 g) and 20 days pregnant Lewis rats (250-330 g). Blood samples (for plasma) and urine were collected serially and analyzed by high-performance liquid chromatography for A, A glucuronide and A sulfate. Serum inorganic sulfate concentrations were determined in a separate study. With respect to the 300-mg/kg dose, pregnant animals exhibited a significant decrease in relative (body weight normalized) total clearance and no change in absolute total clearance, no change in relative apparent volume of distribution and a significantly increased biological half-life. As a fraction of the administered dose, pregnant animals excreted more A, less A sulfate and the same fraction of A glucuronide as did nonpregnant animals. Pregnancy had no apparent effect on base-line serum inorganic sulfate concentration. Both normal and pregnant rats became inorganic sulfate-depleted after injection of A, 300 mg/kg. The relative total clearance of the 300-mg/kg dose of A decreased with increasing litter size, whereas the relative apparent volume of distribution was unaffected. The relative total clearance of a 15 mg/kg dose of A was much higher than that of the 300-mg/kg dose and approximated liver plasma flow rate; it was not changed by pregnancy. The relative renal clearances of A glucuronide, A sulfate and creatinine were decreased in pregnancy, whereas the absolute renal clearances of the two conjugates and creatinine were unaffected. Comparative assessment of the effect of pregnancy on the pharmacokinetics of A and other drugs in different species requires consideration of possible dose dependence and of the implications of normalizing clearance and volume of distribution values.