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1. The aim of this study was to investigate whether blood-brain barrier transport of morphine was affected by the absence of mdr1a-encoded P-glycoprotein (Pgp), by comparing mdr1a (-/-) mice with mdr1a (+/+) mice. 2. Mdr1a (-/-) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic-no-net-flux method. 3. Retrodialysis loss of morphine and nalorphine was similar in vivo. Unbound brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with corresponding total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic-no-net-flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (-/-) and (+/+) mice, respectively. 4. No significant differences in the pharmacokinetics of the metabolite morphine-3-glucoronide were observed between (-/-) and (+/+) mice. 5. In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood-brain barrier.

Purpose: The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by microdialysis (MD)., Methods: Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery., Results: Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 +/- 0.25 and 0.95 +/- 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 +/- 0.12 for the exponential infusion. The half-lives were 25 +/- 4 min, 22 +/- 2 min in blood and 27 +/- 5 min, 25 +/- 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 +/- 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCblood,morphine/AUCblood,codeine ratio of 7.7 +/- 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure., Conclusions: Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.

The permeability of human thoracic and lumbar dura mater to various compounds in clinical use was determined in vitro. Sections of dura mater, 3 to 4 cm in diameter, obtained at post-mortem were placed between the ports (area = 3 cm2) of two glass chambers (A and B) which fitted tightly together to form a two-chamber apparatus for measuring permeability through the dura. Each chamber contained 5 ml of artificial cerebrospinal fluid. A sample of test drug solution was introduced into one chamber (A) and 50 microliters aliquots were withdrawn from the other chamber (B) at predetermined intervals. Permeability was determined by calculating the rate of diffusion (slope) from the plot of mean drug concentration (chamber B) versus time. Dura mater permeability was shown to be a simple diffusion process and to be independent of lipid-solubility and molecular weight. Permeability appeared to increase with age and may have a linear relationship to the initial concentration.

A sensitive taste conditioning test was used to measure the aversive effect of a single intraventricular (i.c.v.) or subcutaneous (s.c) injection of an opioid antagonist that readily crosses the blood brain barrier (naltrexone), and one of two that do not (methylnaltrexone and diallylnormorphinium). This was done in drug-naive rats and in rats implanted 5 days earlier with a pellet containing 75 mg morphine. It was found that the morphine exposure had no significant effect on the dose-response curve of the taste aversion produced by s.c. methylnaltrexone and s.c. diallynormorphinium but reduced the lowest effective dose for the other antagonist treatments from three to more than 100 times. Consideration of the data, together with the pharmacokinetic properties of the drugs and the routes of administration used, supported a conclusion that only those aversions involving central antagonist activity show the potentiation effect of chronic morphine treatment. The findings were also discussed with regard to the location of receptors important for aversions produced by opioid antagonists in naive rats.

A capillary column gas chromatographic method is described for the simultaneous determination of morphine, codeine, heroin, 3- and 6-monoacetylmorphine, nalorphine, naloxone, ethylmorphine, and naltrexone. The drugs were extracted from 2 ml plasma, urine, or other biological samples, including tissue under alkaline conditions in chloroform-isopropanol-n-heptane (50:17:33, v/v), with levallorphan as an internal standard. The drugs were extracted into acid and then reextracted into chloroform after the acid had been alkalinized. After derivatization with trifluoroacetic anhydride, an aliquot was injected into a 25m capillary column equipped with a nitrogen phosphorus detector. The lower limits of detectability, extraction recovery, and the within-run and day-to-day precision of results were determined for each drug. Our results indicate that the procedure is suitable for use in overdose screening and therapeutic drug monitoring.

Different processes are involved in renal and hepatic excretion of organic anions and cations. In contrast to our knowledge of anion excretion, information about cation transport in kidney and liver is relatively scarce. In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.