Transport of narcotic analgesics by choroid plexus and kidney tissue in vitro☆
Abstract
Radioactive narcotic analgesics, including morphine, dihydromorphine, nalorphine, codeine, levorphan, dextrorphan, and l-methorphan were accumulated against an apparent concentration gradient in pieces of rabbit and dog choroid plexus and in slices of dog renal cortex by a metabolically dependent mechanism. The uptake of dihydromorphine by these tissues in vitro was a saturable process depressed by low temperatures, a nitrogen atmosphere, and certain metabolic inhibitors. It also was competitively inhibited by nalorphine and by any one of several organic bases which previously have been demonstrated to be actively transported by these tissues. Under certain conditions, stimulation of dihydromorphine uptake by choroid plexus was produced by organic bases. The transport in choroid plexus of one of these organic bases, hexamethonium, was competitively inhibited by dihydromorphine. Studies with levorphan and dextrophan indicated an element of stereospecificity in their accumulation by choroid plexus. Thus it is concluded that the narcotic analgesics share the same active transport mechanisms described for a variety of organic bases that are accumulated in choroid plexus and renal tissue in vitro. Suggestions are made relative to the significance of these observations for the intact animal.
References (35)
- Y. Tochino et al.
Biochem. Pharmac.
(1965) - L.S. Schanker et al.
Life Sciences
(1962)L.S. Schanker et al.Life Sciences
(1962) - O. Steinwall
Acta psychiat. scand.
(1961) - C.C. Hug et al.
J. Pharmac. exp. Ther.
(1965) - L. Peters
Pharmac. Rev.
(1960) - Y. Tochino et al.
Am. J. Physiol.
(1965) - K. Welch
Am. J. Physiol.
(1962) - C.C. Hug et al.
Univ. Mich. med. Bull.
(1963) - L.B. Mellett
Pharmacologist
(1963) - K.S. Andersen et al.
J. org. Chem.
(1959)
J. Pharmac. exp. Ther.
J. Pharmac. exp. Ther.
J. Pharmac. exp. Ther.
Am. J. Physiol.
Pharmac. Rev.
Am. J. Physiol.
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Uptake and metabolism of cisplatin by rat kidney
1984, Kidney InternationalUptake and metabolism of cisplatin by rat kidney. Cisplatin, an effective antineoplastic agent, is toxic to the kidney. Since the kidney's vulnerability to cisplatin may originate in its ability to accumulate and retain platinum to a greater degree than other organs, we studied the characteristics of the renal accumulation of platinum and investigated the nature of intracellular platinum. Cisplatin and ethylenediammine-dichloroplatinum, nephrotoxic and antineoplastic liganded platinum compounds, were concentrated in rat renal cortical slices fivefold above medium concentration. Platinum uptake was energy- and temperature-dependent and could be inhibited by drugs which inhibit base transport. The organic anions para-aminohippurate and pyrazinoate did not reduce renal slice platinum uptake. Unbound platinum in the blood and urine was predominantly cisplatin but unbound platinum in kidney cytosol was not. This latter compound, in contrast to cisplatin, was not active as a mutagen. These studies suggest that the kidney accumulates platinum in part by transport or specific binding to the base transport system in the kidney and biotransforms it intracellularly. Unbound platinum in the cell is not cisplatin and may no longer be toxic.
Captation et métabolisme du cisplatine par le rein de rat. Le cisplatine, un agent anti-néoplasique efficace, est toxique pour le rein. Puisque la vulnérabilité du rein au cisplatine pourrait provenir de sa capacité d'accumuler et de conserver le platine à un degré plus élevé que d'autres organes, nous avons étudié les caractéristiques de l'accumulation rénale de platine et cherché la nature du platine intra-cellulaire. Le cisplatine et l'éthylènediamminedichloroplatine, des composés néphro-toxiques et anti-néoplasiques liés au platine, étaient concentrés dans des tranches corticales rénales de rat cinq fois plus que la concentration du milieu. La captation du platine était dépendante de l'énergie et de la température, et pouvait être inhibée par des médicaments qui inhibent le transport des bases. Les anions organiques para-aminohippurate et pyrazinoate ne diminuaient pas la captation du platine par les tranches rénales. Le platine non lié dans le sang et l'urine était de façon prédominante du cisplatine, mais le platine non lié dans le cytosol de rein n'en était pas. Ce dernier composé, contrairement au cisplatine, n'était pas actif en tant que mutagène. Ces études suggèrent que le rein accumule le platine en partie par un transport ou par une liaison spécifique au système de transport des bases dans le rein, et le biotransforme dans les cellules. Le platine non lié dans la cellule n'est pas du cisplatine et pourrait ne plus être toxique.
Effects of morphine and pentobarbital on mouse and rat renal transport systems
1979, Toxicology and Applied PharmacologyThe effects of morphine and pentobarbital administered by pellet implantation have been examined for possible nephrotoxic effects in the rat and the mouse. In particular, the effects of these drugs on various renal transport mechanisms were examined. Morphine was found to disrupt renal transport, tissue electrolytes, but not tissue oxygen consumption 24 hr after pellet implantation in the mouse. By 72 hr, however, all parameters examined had returned to control levels despite the continued presence of morphine. The specificity of this effect was demonstrable through the use of naloxone. This antagonist reversed completely all of the morphine effects in the mouse. In the rats, morphine altered only p-aminohippurate (PAH) transport. Pentobarbital reduced PAH and tetraethylammonium (TEA) transport in the rat. Kidney slices from mice implanted with pentobarbital showed significant increases in the uptake of PAH and α-aminoisobutyrate (AIB). No disruption of tissue electrolytes or water was observed in either species with pentobarbital administration.
The accumulation of (<sup>3</sup>H) enkephalinamide (2-D-alanine-5-methioninamide) in rat brain tissues
1978, NeuropharmacologyThe accumulation of D-Ala2-Met-enkephalinamide (tyrosylring-2-6, 3H) in cerebral cortex slices and isolated choroid plexus of rats was investigated. The accumulation of enkephalinamide is against a concentration gradient, and it is inhibited by some metabolic inhibitors. The saturable accumulation process is stronger in choroid plexus than in cerebral cortex slices. At the concentration of 1 × 10−5M, naloxone and levorphanol but not morphine and dextrorphan decrease enkephalinamide accumulation. Free sodium and magnesium ions have no effect on the accumulation of enkephalinamide, but free calcium ions decrease the accumulation in choroid plexus. Three dipeptides that are part of enkephalinamide have no effect on enkephalinamide accumulation, but tyrosine decreases the accumulation in choroid plexus. The accumulation of enkephalinamide in brain tissues shows some similarity to that of opiates.
The uptake of Δ<sup>9</sup>-tetrahydrocannabinol in choroid plexus and brain cortex in vitro and in vivo
1976, Brain Research[3H]Δ9Tetrahydrocannabinol (Δ9-THC) was actively transported by the choroid plexus and cerebral cortical slices of the rabbit when incubated as a BSA-microsuspension in artificial rabbit CSF. The transport system forΔ9-THC in choroid plexus had aVmax of 174 nmoles/mg tissue/h, approximately 9-fold greater than that observed for cortical slices.In vivo experiments demonstrated a preferential distribution of Δ9-THC in choroid plexus at 1 h after intravenous injection. These results indicate thatΔ9-THC is actively accumulated by choroidal epithelium and may also be transported across the epithelial stroma into the capillary circulation. This suggests that the choroid plexus participates in the regulation ofΔ9-THC concentration in CSF and indirectly in brain by means of the ‘sink’ function of the CSF.
Factors affecting morphine uptake into kidney slices
1976, Biochemical PharmacologyThe uptake of [n-methyl14C]morphine by mouse kidney slices was saturable, reversible, temperature- and pH-dependent, and was inhibited by strong metabolic poisons and by structural analogs, thereby satisfying criteria for mediation by active transport processes. There were species differences: rat kidney cortex slices took morphine up at rates similar to those of mouse kidney, but guinea pig kidney cortex had lower uptake. Thin-layer chromatography (t.l.c.) of slice extracts after incubation with [14C]morphine did not indicate significant metabolism of morphine. Morphine efflux after equilibrium uptake from 30 nM or 10 μM initial medium levels required 20 min for 50 per cent of the [14C]morphine to exit. The uptake at 5 min was proportional to the equilibrium level at 30 min from 5 nM to 10 μM. No evidence for counter-transport was observed. Tissue/medium levels of 10–12 at 39–90 nM morphine (after 30 min at 37°) were reduced 50 per cent at pH 6.5 or at 20°, or by mitochondrial enzyme inhibitors, e.g. rotenone. Narcotic antagonists and analogs (methadone, nalorphine and levorphanol) and quinine also reduced the uptake of morphine from medium levels of 0.01 to 0.1 μM. However, at morphine concentrations above 10 μM, narcotic analogs or antagonists up to 50 μM did not inhibit uptake. Transport system inhibitors, quarternary bases, reducing agents and SH-oxidants also inhibited morphine uptake from 30 nM to 0.5 mM. Phloretin, phloridzin and atractyloside did not block uptake, while glucose, ouabain and NaF were very weak inhibitors. The results suggest that uptake of morphine in kidney slices involves SH groups and mitochondrial activity rather than glycolytic or ion-pump mechanisms. With a few exceptions, the characteristics and inhibitor sensitivity of morphine uptake by kidney slices and of amino acid uptake by brain slices appear similar.
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A summary of the work presented in detail here appeared in Fedn Proc. 25, 415 (1966). This investigation was supported in part by Research Grant MH-08580 from the National Institutes of Health. The investigator is a Postdoctoral Research Scholar of the American Cancer Society.