Results indicated that administration of morphine as a constant-rate IV infusion at a dose of 0.12 mg/kg/h induced effects similar to those obtained with administration at a dose of 1 mg/kg, IM, every 4 hours in dogs undergoing laparotomy. Panting was attributed to an opioid-induced resetting of the hypothalamic temperature set point, rather than respiratory depression.

This study examines the potential for the phytoestrogenic isoflavones, a type of complementary medicine, to be involved in pharmacokinetic interactions in the liver. Rat livers were isolated and perfused to steady state, in single-pass mode, with either 5 microM paracetamol (n = 6), or 5 microM paracetamol with a 50:50 molar mixture of genistein and biochanin A or daidzein and formononetin, at a total isoflavone concentration of 1 and 10 microM (n = 6 for each mixture at each concentration). At 1 microM, neither isoflavone mixture had any effect, while at 10 microM both mixtures decreased the clearance of paracetamol and the formation clearance to paracetamol sulfate. Genistein and biochanin A (10 microM) also increased the biliary extraction of hepatically-generated paracetamol sulfate. Additional livers were perfused with an infusion of 5 microM (14)C-paracetamol in the absence (n = 4), or presence, of a 10 microM genistein and biochanin A mixture (n = 4). Analysis of washout perfusate and bile samples (up to 30 min after stopping the infusion) revealed that the isoflavones reduced the first-order rate constant for paracetamol sulfate transport into perfusate, but not for transport into bile. The results indicate that isoflavones can reduce the formation of paracetamol sulfate and that its enhanced excretion into bile arises from the inhibition of sinusoidal efflux transport.

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Foods and complementary medicines contain phytoestrogenic isoflavones such as genistein, which undergo hepatic glucuronidation and excretion into bile and can potentially interfere with the hepatic elimination of other compounds. To investigate this potential, livers from Sprague-Dawley rats were perfused in single-pass mode with preformed gemfibrozil 1-O-acyl glucuronide (GG) (1 microM, n = 12) for 60 min followed by a 30-min washout phase, or with gemfibrozil (1 microM, n = 10) for 120 min. Half of each group of livers were co-perfused with genistein (10 microM) throughout the experiment. Perfusate and bile were analyzed for GG and gemfibrozil by HPLC. Co-perfusion with genistein significantly (P< 0.05) decreased the biliary extraction ratio of preformed GG from a mean of 0.82 to 0.65 and the first-order rate constant for transport of GG into bile from 0.054 +/- 0.010 to 0.032 +/- 0.008 min(-1), but increased the first-order rate constant for sinusoidal efflux of GG from 0.128 +/- 0.023 to 0.227 +/- 0.078 min(-1). Co-perfusion with genistein also significantly decreased the biliary extraction ratio of hepatically generated GG from 0.95 +/- 0.01 to 0.83 +/- 0.05. The findings confirm that genistein increases the potential for hepatic and systemic exposure to hepatically generated glucuronides, which may be important for patients on conventional drugs who consume isoflavones.