Received for publication June 9, 2004.
Revised August 5, 2004.
Accepted for publication August 17, 2004.

THE EFFECT OF ANESTHESIA AND SURGERY ON CYP3A ACTIVITY IN RATS

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 hours after anesthesia with ketamine/xylaxine and surgery for placement of indwelling vascular and duodenal catheters (acute) 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 four to six hours 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 to the chronic animals (0.33 ± 0.07, P = 0.001). Hepatic availability was determined using a classical approach where F_H was calculated from the AUC ratio after portal venous and intravenous administration. F_H was higher in the acute rats (0.48) compared to 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 to 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 indicator dye dilution method after infusion of [¹⁴C]-PEG 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 three days of surgery and anesthesia, are conducted under non-physiologic conditions and therefore provide inaccurate assessment of drug disposition, in particular, clearance and bioavailability.

Key words: anesthetics, bioavailability, CYP3A, drug disposition, hepatic elimination, in vivo probes, physiologically-based pharmacokinetics

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