Absorption and Metabolism of Allopurinol and Oxypurinol by Rat Jejunum <i>in Vitro</i>: Effects on Uric Acid Transport

Shaw, M. I.; Parsons, D. S.

doi:10.1042/cs0660257

Cited by 9 publications

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“…The presence of oxypurinol in the lumen decreased the serosal appearance of exogenous uric acid, but the presence of uracil did not. The failure of allopurinol to affect the movement of uric acid is at variance with several reports in the literature in which it has been shown to reduce the secretion of hypoxanthine in guinea-pig intestine (Kolassa et al 1980), to decrease the uptake of guanine in pig intestine (Simmonds et al 1973) and uric acid in rat intestine (Shaw & Parsons, 1984a).…”

Section: Uracilmentioning

confidence: 58%

“…Isocratic reverse phase chromatography with a 25 cm Hypersil 5 ODS analytical column (Anachem) fitted with a 5 cm guard column (dry packed with Lichropret (Anachem) in the laboratory) was used. Conditions of separation, the elution profiles, quantification and identification of the chromatographic peaks were as described by Shaw & Parsons (1984a).…”

Section: Chromatographymentioning

confidence: 99%

“…The effects that drugs normally used in the treatment of hyperuricaemia might have on transport is also unclear. Several reports have indicated that purine transport in the intestine may be altered in the presence of structurally related compounds (Schanker, Jeffrey & Tocco, 1963;Simmonds, Rising, Cadenhead, Hatfield, Jones & Cameron, 1973; Kolassa, Schutzenberger, Wiener & Turnheim, 1980;Shaw & Parsons, 1984a).…”

Section: Introductionmentioning

confidence: 99%

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The transport of uric acid across mouse small intestine in vitro.

Bronk¹,

Shaw²

1986

The Journal of Physiology

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The in vitro recirculation technique was used to study the uptake and transport of uric acid by the jejunum of mouse small intestine. Three components of the serosal secretions appeared to be endogenously derived nucleic acid derivatives; two of these were identified as uric acid and uracil. There was no detectable metabolism of uric acid by the intestine. Uric acid transported from the lumen appeared in the serosal fluid at a concentration higher than that in the lumen. The final serosal/luminal concentration ratio of about 1.18 for exogenous uric acid was found to be constant over the concentration range studied (0.01-0.1 mM). The presence of exogenous uric acid in the lumen did not affect the production of endogenous uric acid by the intestine and its release into the serosal secretions. Mucosal concentration of exogenous uric acid was below, but the total mucosal concentration (exogenous+endogenous) was above, that in the lumen. There was no evidence for the secretion of endogenous uric acid into the lumen. Oxypurinol significantly decreased the rate of serosal appearance of exogenous uric acid. Allopurinol did not affect the transport of exogenous uric acid from the lumen and there was negligible metabolism of allopurinol to oxypurinol by the tissue. Uracil did not affect the transport of exogenous uric acid from the lumen, or the serosal appearance of endogenous uric acid. Likewise uracil transport was unaffected by luminal uric acid.

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Section: Uracilmentioning

confidence: 58%

Section: Chromatographymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The transport of uric acid across mouse small intestine in vitro.

Bronk¹,

Shaw²

1986

The Journal of Physiology

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“…The function of MRP4 may have different implications depending on the tissue and side of cell membrane in which MRP4 is expressed. MRP4 expressed apically in the intestine might be a site where allopurinol stimulates the luminal efflux of urate ( Shaw and Parsons, 1984 ; Li et al ., 2007 ). In vascular smooth muscle, where urate is taken up by URAT1 ( Price et al ., 2006 ), efflux through MRP4 could have an important function in regulating intracellular urate levels.…”

Section: Discussionmentioning

confidence: 99%

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

El-Sheikh

Heuvel

Koenderink

et al. 2008

British J Pharmacology

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Background and purpose: The xanthine oxidase inhibitors allopurinol and oxypurinol are used to treat hyperuricaemia, whereas loop and thiazide diuretics can cause iatrogenic hyperuricaemia. Some uricosuric drugs and salicylate have a bimodal action on urate renal excretion. The mechanisms of action of these hypo-and hyperuricaemic drugs on the handling of urate in renal tubules have not been fully elucidated. Recently, we identified the multidrug resistance protein (MRP) 4 as a luminal efflux transporter for urate in the proximal tubule. Experimental approach: Here, we studied the effect of these drugs on [ 14 C]urate transport using human embryonic kidney 293 cells overexpressing human MRP4 and in membrane vesicles isolated from these cells. Key results: Allopurinol stimulated MRP4-mediated cellular urate efflux and allopurinol and oxypurinol both markedly stimulated urate transport by MRP4 in membrane vesicles. Bumetanide and torasemide had no effect, whereas furosemide, chlorothiazide, hydrochlorothiazide, salicylate, benzbromarone and sulfinpyrazone inhibited urate transport, at concentrations ranging from nanomolar up to millimolar. Probenecid stimulated urate transport at 0.1 mM and inhibited transport at higher concentrations. Conclusions and implications: These data suggest that inhibition of MRP4-mediated urate efflux by furosemide and thiazide diuretics could have an important function in their hyperuricaemic mechanisms. Furthermore, stimulation of MRP4-mediated renal urate efflux could be a new mechanism in the hypouricaemic action of allopurinol and oxypurinol. In conclusion, MRP4 may provide a potential target for drugs affecting urate homoeostasis, which needs to be further evaluated in vivo.

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“…Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU Transport of the purines uric acid, xanthine and hypoxanthine across the small intestine is said to be entirely passive (Khan, Wilson & Crawhall, 1975) but there is also evidence that purine transport is modified in the presence of related compounds, e.g. a decrease in uptake of urate by rat jejunum in the presence of the hypoxanthine analogue allopurinol and the xanthine analogue oxypurinol has been reported (Shaw & Parsons, 1984a).…”

Section: Pmentioning

confidence: 99%

Proceedings of the Physiological Society and the Societa Italiana Di Fisiologia, 11‐13 July 1985, Oxford Meeting: Communications

1985

The Journal of Physiology

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(1932) first noted a respiratory grouping of cervical sympathetic nerve discharge. Recordings from single fibres in the cervical sympathetic nerve of the cat (Preiss, Kirchner & Polosa, 1975) show that some neurones fire maximally during inspiration and others during expiration. Furthermore, shifts in antidromic latency indicate that both spontaneously active and silent preganglionic neurones receive an input related to central respiratory drive (Lipski, Coote & Trzebski, 1977). In the present investigation the activity of spontaneously active and glutamate-activated silent sympathetic preganglionic neurones has been analysed for firing patterns related to central respiratory drive in order to determine whether they receive similar phasic inputs.In 19 ac-chloralose-(100 mg/kg i.v.) anaesthetized rats the activity of fifty-two antidromically identified cervical sympathetic preganglionic neurones was recorded in Th2 segment of the spinal cord using multibarrelled micropipettes as described by Gilbey, Coote, Fleetwood-Walker & Peterson (1982). The animals were paralysed with gallamine triethiodide and artificially ventilated with 02-enriched room air. Phrenic nerve discharge was recorded as an indication of central respiratory drive. Some animals were given a pneumothorax and were vagotomized. End-tidal CO2 and blood gases were monitored. Thirty-two neurones were shown to have a phrenic-related discharge pattern on the basis of phrenic-triggered histograms. One group of twelve neurones fired maximally during phrenic nerve activity; of these, four were silent but were induced to fire by the ionophoresis of glutamate. The other group of twenty neurones fired maximally during phrenic silence, of which six were glutamate-activated. In each group spontaneously active and glutamate-activated neurones had similar firing patterns.The present experiments show that, in the rat as in the cat, some sympathetic preganglionic neurones receive phasic inputs related to central respiratory drive which exert a marked control over their output. By raising their excitability, by the ionophoresis of glutamate, the central respiratory-drive-related inputs to silent sympathetic preganglionic neurones have been shown to be similar, if not identical, to those received by spontaneously active neurones.

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Absorption and Metabolism of Allopurinol and Oxypurinol by Rat Jejunum in Vitro: Effects on Uric Acid Transport

Cited by 9 publications

References 0 publications

The transport of uric acid across mouse small intestine in vitro.

The transport of uric acid across mouse small intestine in vitro.

Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4

Proceedings of the Physiological Society and the Societa Italiana Di Fisiologia, 11‐13 July 1985, Oxford Meeting: Communications

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