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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 [ 14 C]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.During drug development, in vivo drug absorption and hepatic first-pass metabolism studies commonly are performed in rats, dogs, and primates after surgical manipulation to implant vascular and gastrointestinal catheters. The absorption and bioavailability of orally administered drugs is dependent on intestinal and liver function, including metabolism. The ability to quantify the extent and variability of first-pass metabolism and the inhibition of metabolism in vivo are important for the development of oral dosage forms. To separately determine the effects of the liver on hepatic first-pass metabolism from the contribution by the gut, the area under the plasma concentration versus time curve (AUC) following drug administration via the portal vein is compared with the AUC obtained after oral and intravenous drug administration. These experiments are typically conducted using rodents and are often conducted shortly after the animal has regained its righting reflex. Consciousness and mobility, not gastrointestinal or liver function, are therefore frequently used as parameters of surgical recovery. Although studies have clearly demonstrated tha...

Graphical abstract

The cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive. Experimental Approach: Male rats and wild-type and TRPV1 knockout mice with peripheral nerve injury-sciatic nerve axotomy and spinal nerve ligation in rats; chronic constriction injury (CCI) in miceprovided models of chronic neuropathic pain. Ipsilateral lumbar (L)4-5 DRGs were assayed for activin C expression. Chronic neuropathic pain animals were treated with intrathecal or locally pre-administered activin C or the vehicle. Nociceptive behaviours and pain-related markers in L4-5 DRGs and spinal cord were evaluated. TRPV1 channel modulation by activin C was measured. Key Results: Following peripheral nerve injury, expression of activin βC subunit mRNA and activin C protein was markedly up-regulated in L4-5 DRGs of animals with axotomy, SNL or CCI.

Hydroxyl free radicals generated by visible-light-catalyzed water splitting over CoP/CdS drive the oxidation of arylalcohols with hydrogen evolution.