Investigations on the hepatic uptake systems for organic cations with a photoaffinity probe of procainamide ethobromide

Mol, Wim E.M.; Müller, Michael; Kurz, Gerhart; Meijer, Dirk K. F.

doi:10.1016/0006-2952(92)90181-h

Cited by 11 publications

(5 citation statements)

References 24 publications

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“…The organic cations chosen in this study comprised TBuMA 32 and APM, 26 which are categorized as type 1 cationic compounds with regard to hepatic uptake mechanisms, 32 and the other two model compounds, vecuronium and APDA, which are considered type 2 cationic compounds with regard to their hepatic uptake mechanisms. 29 The categorization of the studied organic cations was recently confirmed for the type 1 drugs such as TBuMA (personal communication, H. Koepsell, Wü rzburg, Germany) 33 and for the type 2 cationic drugs such as APDA 34,35 and vecuronium (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…Vecuronium was a gift from Organon Teknika (Turnhout, Belgium), and [ 3 H]vecuronium was provided by Organon International (Oss, The Netherlands). Tri-n-butylmethylammonium (TBuMA) and [ 3 H]TBuMA were synthesized in our laboratory, according to the procedures described by Neef et al 25 Azidoprocainamide methoiodide (APM) was synthesized according to the method of Mol et al 26 Azopentyldeoxyajmalinium (APDA) was obtained from Dr. G. Kurz (Freiburg, Germany). 18 Hypnorm was purchased from Janssen Pharmaceuticals (Tilburg, The Netherlands), and diazepam was from Dumex B.V. (Hilversum, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

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Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene disruption

Smit¹,

Schinkel

Müller³

et al. 1998

Hepatology

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In the mouse, both the mdr1a and the mdr1b gene encode drug-transporting P-glycoproteins. The mdr1a P-glycoprotein is expressed in epithelial cells of, among others, the liver and the intestine. Furthermore, the mdr1b gene product is found in the liver but is not detectable in the intestine. To establish the potential involvement of P-glycoprotein in the elimination of cationic amphiphilic drugs from the body, we investigated biliary, intestinal, and urinary excretion in mice with a homozygous disruption of the mdr1a gene (mdr1a(؊/؊) mice ). These mice are fully viable under laboratory conditions and have normal bile flow. Cumulative biliary excretion (expressed as percent of the intravenously administered dose excreted over a 1-hour period) of several cationic compounds was decreased as follows in mdr1a(؊/؊) mice compared with the wild-type animals: tri-n-butylmethylammonium (TBuMA), 0.7% versus 2.1%; azidoprocainamide methoiodide (APM), 3.8% versus 7.6%; and vecuronium, 22.7% versus 41.3%. The luminal secretion of both TBuMA and APM in the small intestine was profoundly decreased, respectively 4.6-fold (1.8% vs. 8.2% in the wild-type) and 7.9-fold (1.6% vs. 10.3% in the wild-type) in mdr1a(؊/؊) mice. Thus mdr1a P-glycoprotein contributes substantially to the removal of a wide variety of cationic agents from the body through intestinal and hepatobiliary secretion, but it evidently acts in concert with other transport system(s). These processes probably provide a protective mechanism limiting the overall rate of absorption as well as the bioavailability of potentially toxic organic

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene disruption

Smit¹,

Schinkel

Müller³

et al. 1998

Hepatology

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“…(1) The substrate specificities reported in the past are similar. Quinine is slightly more potent than quinidine (Eaton and Klaassen 1978;Mol et al 1992;Nakamura et al 1994). (2) Both mechanisms operate independently of extracellular sodium (Eaton and Klaassen 1978;Takano et al 1984;Wright and Wunz 1987;Oude Elferink et al 1995) but seem to be electrogenic (Grtindemann et al 1994;Moseley et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Transport of small organic cations in the rat liver

Martel

Vetter

Russ

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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The kidneys and the liver are the principal organs for the inactivation of circulating organic cations. Recently, an organic cation transporter (OCT1) has been cloned from rat kidney. In order to answer the question whether OCT1 is involved also in hepatic uptake of organic cations, the pharmacological characteristics of organic cation transport in hepatocytes were compared to the characteristics of transiently expressed OCT1.Primary cultures of rat hepatocytes avidly accumulated the small organic cation 3H-l-methyl-4-phenylpyridinium (3H-MPP+). At equilibrium, the hepatocytes accumulated 3H-MPP+ 56-fold. Initial rates of specific 3H-MPP + transport in hepatocytes were saturable. The half-saturating concentration was 13 ~tmol/1. 3H-MPP+ transport was sensitive to quinine (Ki = 0.79 gmol/1) and cyanine863 (Ki = 0.097 gmol/1). Quinine and cyanine863 are known inhibitors of type I hepatic transport of cationic drugs and of renal excretion of organic cations, respectively. To compare the functional characteristics of 3H-MPP + transport in hepatocytes with those of OCT1, OCT1 has been heterologously expressed and characterized in a mammalian cell line (293 cells). Initial rates of 3H-MPP+ transport were saturable, the Km being 13 gmol/1. The rank order of inhibitory potencies of various inhibitors was almost identical in hepatocytes and 293 cells transiently transfected with OCT1. There was a positive correlation between the Ki's for the inhibition of 3H-MPP+ transport in isolated hepatocytes and transfected 293 cells (r = 0.85; P<0.01; n = 8).The results indicate that OCT1 is functionally expressed not only in the kidney but also in hepatocytes where it is responsible for the transport of small organic cations which, in the past, have been classified as type I substrates.

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“…Tri‐n‐butylmethylammonium (TBuMA) and [ 3 H]‐TBuMA was synthesized in our laboratory, according to the procedures described by Neef et al , (1984a). Azido‐procainamide methoiodide was synthesized according to Mol et al , (1992). Azopentyldeoxy‐ajmalinium (APDA) was obtained from Dr G. Kurz (Freiburg, Germany) (Müller et al , 1994a).…”

Section: Methodsmentioning

confidence: 99%

Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted

Smit

Schinkel

Weert³

et al. 1998

British J Pharmacology

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1 We have used mice with homozygously disrupted mdr1a and mdr1b genes (mdr1a/1b (7/7) mice) to study the role of the mdr1-type P-glycoprotein (P-gp) in the elimination of cationic amphiphilic compounds from the body. These mice lack drug-transporting P-gps, but show no physiological abnormalities under laboratory conditions and have normal bile¯ow. 2 3 H-labelled cationic drugs were administered intravenously (i.v.) to mice as a single bolus dose and the disposition of the studied cationic drugs was investigated by focusing on drug secretion into bile, intestinal lumen and urine. 3 Hepatobiliary secretion of the investigated cationic drugs was profoundly reduced in mice devoid of the mdr1-type P-gps. In fact, the cumulative biliary output, measured during 1 h, of the small type 1 compounds tri-butylmethyl ammonium (TBuMA) and azidoprocainamide methoiodide (APM), as well as of the more bulky type 2 cationic drug vecuronium, was reduced by at least 70% in the mdr1a/1b (7/7) mice compared to wild-type. 4 The intestinal secretion of TBuMA, APM and vecuronium was also profoundly reduced in mdr1a/1b (7/7) mice compared to wild-type mice. The absence of the mdr1-type P-gp resulted in virtual elimination of intestinal secretion of TBuMA and APM (490% reduced as compared to wild-type (P=0.0001 and 0.0022, respectively)). The intestinal secretion of the type 2 cation drug vecuronium was reduced by 58% (P=0.0004) compared to the wild-type mice. 5 Increased renal clearances of both the type 1 compounds TBuMA and APM and also of the type 2 cationic compound vecuronium in the mdr1a/1b (7/7) mice were observed. Furthermore, the balance between hepatic, intestinal and renal clearances of small type 1 organic cations clearly shifted towards a predominant role for renal clearance. Increased renal clearance may be explained by (over)expresion of additional mechanisms for renal organic cation secretion, alternatively they may also point to an as yet unde®ned role of P-glycoprotein in kidney physiology and renal secretory function. 6 We conclude that the elimination from the body of a broad spectrum of cationic amphiphilic drugs via liver and intestine, is largely dictated by the activity of mdr1-type P-glycoproteins.

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Investigations on the hepatic uptake systems for organic cations with a photoaffinity probe of procainamide ethobromide

Cited by 11 publications

References 24 publications

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene disruption

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene disruption

Transport of small organic cations in the rat liver

Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted

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