On the localisation of d-tubocurarine in rat liver lysosomes in vivo by electron microscopy and subcellular fractionation

Weitering, Jeanette G.; Mulder, Gerard J.; Meijer, Dirk K. F.; Lammers, W; Veenhuis, M.; Bonga, S.E. Wendelaar

doi:10.1007/bf00499979

Cited by 19 publications

(4 citation statements)

References 6 publications

(5 reference statements)

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“…40 Others have also shown that rat liver lysosomes sequester certain cations such as tubocurarine. 41 Our experiments with chloroquine, bafilomycin A, and monensin in isolated cell preparations support these findings, demonstrating that after dissipation of the pH gradient, DNR was no longer sequestered within these vesicular compartments. Furthermore, when bafilomycin A was removed, and pH gradients were allowed to recover, DNR again accumu- lated within these vesicular structures.…”

Section: Discussionsupporting

confidence: 75%

Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat

Hayes¹,

Soroka²,

Rios-Velez³

et al. 1999

Hepatology

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In contrast to organic anions, substrates for the canalicular mdr1a and b are usually organic cations and are often sequestered in high concentrations in intracellular acidic compartments. Because many of these compounds are therapeutic agents, we investigated if their sequestration could be regulated. We used isolated perfused rat liver (IPRL), isolated rat hepatocyte couplets (IRHC), and WIF-B cells to study the cellular localization and biliary excretion of the fluorescent cation, daunorubicin (DNR). Despite rapid (within 15 minutes) and efficient (G90%) cellular uptake in the IPRL, only Ϸ10% of the dose administered A major function of the liver is the uptake and biliary excretion of a variety of lipophilic compounds, including endogenous substances such as bilirubin, and exogenous substances such as xenobiotics, drugs, and toxins. Distinct transport proteins are localized on the basolateral and canalicular domains of the hepatocyte to perform this function. 1,2 Many of these transporters have been cloned from rodent and human liver, and most of the canalicular transporters are members of the adenosine triphosphate (ATP) binding cassette super gene family. [3][4][5] These transporters include the multidrug resistance-associated protein, mrp2 or cMOAT, which excretes a variety of amphipathic organic anions 6-8 ; the canalicular bile salt excretory pump (bsep), which promotes ATP-dependent transport of bile salts into bile 9-11 and may be identical with spgp, the sister of P-glycoprotein 12 ; and the P-glycoproteins, mdr1a and 1b, whose endogenous substrates are not known but which transport a variety of organic cations and toxic substances into bile. [13][14][15][16][17] Overexpression of mdr1a and b can occur in cancer cell lines and thereby contribute to resistance to a variety of chemotherapeutic agents. 18 Previous studies have established that some of these excretory transport systems are highly regulated rather than constitutive functions of the hepatocyte, and that compounds such as N 6 ,2Ј-O-dibutyryl-adenosine 3Ј,5Јcyclic monophosphate (DBcAMP) and bile salts are capable of up-regulating their transport capacity. [19][20][21][22] In contrast, inhibitors of microtubule function down-regulate these transport processes. 19,21,23 This type of regulation has been demonstrated for the fluorescent bsep substrate, cholyglycylamidofluorescein (CGamF), and for the mrp2 substrate, glutathione-Smethylfluorescein. 20,21 These findings have led to the conclusion that the plasma membrane transport proteins may also reside on intracellular pericanalicular vesicles, and that apical transport capacity may be regulated by the insertion and/or retrieval of these vesicles to or from the apical canalicular membrane. 21,22,24,25 In the present study, we examined whether the canalicular excretion of the mdr1 transport system can be regulated using the fluorescent mdr1 substrate, daunorubicin (DNR). DNR is a naturally fluorescent organic cation that is widely used as an antineoplastic agent. [26][27][28] Thus, understanding ...

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Section: Discussionsupporting

confidence: 75%

Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat

Hayes¹,

Soroka²,

Rios-Velez³

et al. 1999

Hepatology

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“…Olsen, Chan and Ricker (1975) have shown that metocurine binds extensively to cartilage and chondroitin sulphate. Other workers (Weitering et al, 1975) have found extensive binding of tubocurarine to lysosomes in the liver and this could occur with lysosomes in other tissues and be true for vecuronium.…”

Section: Fig 3 Cumulative Biliary Excretion and Hepatic Content Of mentioning

confidence: 78%

Disposition of Vecuronium Bromide in the Cat

Bencini¹,

Scaf²,

Ágoston³

et al. 1985

British Journal of Anaesthesia

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The disposition of vecuronium bromide has been investigated in six normal cats (group I) and in six cats with ligated renal pedicles (group II). A combined fluorimetric and chromatographic technique was used to determine the concentrations of vecuronium and its metabolites in biological material. After i.v. injection of 0.6 mg kg-1, vecuronium disappeared rapidly from the plasma of the normal cat. Concentrations decreased bi-exponentially with half-lives of 4.6 and 31 min, respectively. The steady state volume of distribution was 0.23 litre kg-1 and the clearance 11 ml min-1 kg-1. Seventy percent of an i.v. dose of vecuronium (or its metabolites) was recovered: 15% in the urine, 40% in the bile and 15% in the liver. Only 3.8% of this consisted of the 3-hydroxy metabolite. There were no significant differences in pharmacokinetic data or in the amounts of vecuronium and its metabolites recovered in cats with ligated renal pedicles. The 15% of vecuronium normally excreted by the kidney was compensated for by increased hepatic and biliary concentration of vecuronium.

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“…Some cationic drugs, such as chloroquine,11 imipramine,21 and D ‐tubocurarine,22 are reported to have shown large distribution volumes and K p values, and those distribution profiles could cause the accumulation of the drugs in certain tissues after their repeated administration. DX‐9065a is a basic drug having both acetimidoyl and amidino groups in its molecule.…”

Section: Discussionmentioning

confidence: 99%

“…To account for the concentrative uptake phenomena of cationic organic compounds in certain tissues, some mechanisms have been proposed in the literature, and they can be categorized into two types: (A) binding to intracellular components of phosphatidylserine,23,24 lysosomes,22,25–29 and mitochondria;21 and (B) uptake by a carrier protein17,30 or a receptor‐mediated endocytosis system 18,31. In many cases, however, the contribution of each mechanism was evaluated solely, and it is, therefore, still unclear which mechanism predominantly accounts for the concentrative distribution profile of the corresponding drug.…”

Section: Discussionmentioning

confidence: 99%