Abstract

The purpose of this investigation was to examine the effects of surgery and anesthesia on in vivo CYP3A activity and portal venous blood flow. Midazolam, a CYP3A probe for both rats and humans, was administered orally (2.7 mg), intravenously (0.57 mg), or via the portal vein (0.57 mg) to rats 4 h after anesthesia with ketamine/xylazine and surgery for placement of indwelling vascular and duodenal catheters and 3 days after surgery (chronic). The systemic clearance of midazolam was 51 ± 4 ml/min/kg in the chronic animals, and this was significantly decreased (29 ± 1 ml/min/kg, P = 0.024) in acute rats studied 4 to 6 h after anesthesia and surgery. The hepatic availability (F_H), directly determined from the aortic and hepatic venous concentration gradient, was significantly higher in the acute animals (0.57 ± 0.05) compared with the chronic animals (0.33 ± 0.07, P = 0.001). Hepatic availability was determined using a classical approach in which F_H was calculated from the area under the plasma concentration versus time curve ratio after portal venous or intravenous administration. F_H was higher in the acute rats (0.48) compared with the chronic animals (0.27 ± 0.03). Portal venous blood flow was significantly lower in the acute animals (5.0 ± 0.4 ml/min/100 g body weight) compared with the chronic animals (9.1 ± 0.9 ml/min/100 g body weight, P = 0.015). The effect of surgery and anesthesia was confirmed using the indicator dye dilution method after infusion of [¹⁴C]polyethylene glycol 4000 into the superior mesenteric artery. Our data suggest that anesthesia and surgery decreases both hepatic CYP3A activity and hepatic blood flow in rats. Studies performed in rats within 3 days of surgery and anesthesia are conducted under nonphysiologic conditions and therefore provide inaccurate assessment of drug disposition, in particular, clearance and bioavailability.