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Biomedical subjects

J W Smit

Publications and source records attributed to J W Smit.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mrp2 is essential for estradiol-17beta(beta-D-glucuronide)-induced cholestasis in rats.

The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17beta(beta-D-glucuronide) (E(2)17G). Administration of ¿(3)HE(2)17G (18 nmol/g body weight) gave a similar degree of cholestasis and biliary excretion of E(2)17G-equivalents in wild-type and Mdr1a(-/-)/1b(-/-) mice. When expressed in Sf9 cells, Bsep-mediated adenosine triphosphate (ATP)-dependent transport of taurocholate (TC, 1 micromol/L) in membrane vesicles was 110% +/- 12.5% and 108% +/- 17.3% of control in the presence of 10 and 50 micromol/L E(2)17G, respectively, whereas in rat canalicular membrane, both E(2)17G and the choleretic estradiol-3-beta-D-glucuronide (E(2)3G) inhibited ATP-dependent transport of TC to the same extent. Infusion of ¿(3)HE(2)17G (24 micromol) did not induce cholestasis in Mrp2-deficient TR(-) rats whereas 2 micromol of ¿(3)HE(2)17G inhibited bile flow by 51% in control Wistar rats. The maximal biliary concentration of E(2)17G was 3.5 and 2.5 mmol/L in control and TR(-) rats, respectively. However, 2.2 mmol/L of E(2)17G in bile is associated with inhibition of bile flow in control rats. These data show that (1) Mdr1a/1b are not essential for E(2)17G-mediated cholestasis, (2) direct inhibition of Bsep-mediated bile acid transport is not the mechanism for E(2)17G cholestasis, and (3) accumulation of E(2)17G in bile alone is not sufficient to induce cholestasis. These data indicate that the process of Mrp2-mediated transport of high concentrations of E(2)17G is essential for its induction of cholestasis.

ATP-Binding Cassette Transporters↗
PubMed2000

Reestablishment of in vitro and in vivo iodide uptake by transfection of the human sodium iodide symporter (hNIS) in a hNIS defective human thyroid carcinoma cell line.

Uptake of iodide is a prerequisite for radioiodine therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium iodide symporter (hNIS). Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. In this study, we report the stable transfection of a hNIS expression vector into the hNIS defective follicular thyroid carcinoma cell line FTC133. Stablely transfected colonies exhibited high uptake of Na125I, which could be blocked completely with sodiumperchlorate. hNIS mRNA expression corresponded with iodide uptake in semiquantitative polymerase chain reaction. Iodide uptake was maximal after 60 minutes, whereas iodide efflux was complete after 120 minutes. hNIS transfected FTC133 and control cell lines injected subcutaneously in nude mice formed tumors after 6 weeks. Iodide uptake in the hNIS transfected tumor was much higher than in the nontransfected tumor, which corresponded with hNIS mRNA expression in tumors.

Adult↗
PubMed2000

Clinical outcome after standardized versus dosimetric radioiodine treatment of hyperthyroidism: an equivalence study.

The aim of this study was to investigate the equivalence in outcome of standardized versus uptake-adjusted dosing of radioactive iodine (131I) for hyperthyroidism. We performed a 1-year follow-up study of two patient cohorts: 326 patients referred for 131I treatment of hyperthyroidism in Graves' disease (GD; n=216) or toxic multinodular goitre (TMG; n=110) in the period June 1995 to January 1998. Of these patients 128 were treated according to a standardized regimen, based on palpated thyroid volume and diagnosis, and 198 with a 131I uptake-adjusted dosimetric method. The incidence of hypothyroidism, euthyroidism or recurrence of disease was recorded. In Graves' disease hypothyroid outcome in the standardized versus adjusted method was 40.7% vs 44.6% (95% CI difference, -17.4 to +9.5%); it was 67.4% vs 70.8% (95% CI difference -15.9 to +9.3%) for all non-euthyroid outcomes. In TMG, due to wide confidence interval ranges a conclusion of equivalence could be made only for recurrence of hyperthyroidism (mean -3.2%, 95% CI, -13.8 to +7.5%). A simplified dosage method for 131I treatment of hyperthyroidism, which omits 131I uptake adjustment, may improve procedure efficiency and patient convenience, and leads to an equivalent outcome in GD and probable equivalent outcome in TMG.

Adult↗
PubMed2000

Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications.

The multidrug resistance protein BCRP (breast cancer resistance protein) is a member of the ATP-binding cassette family of drug transporters. Overexpression of BCRP caused by exposure of cells to mitoxantrone (MX) or doxorubicin/verapamil resulted in a resistance pattern that is different from what is generally seen in the case of P-glycoprotein and MRP1 overexpression. Recently, the BCRP gene has been described in ovarian, breast, colon, and gastric cancer and fibrosarcoma cell lines. Our human tumor cells T8 and MX3, derived from the ovarian cancer cell line IGROV1 by stepwise increased exposure to topotecan and MX, are resistant to topotecan, CPT11, SN38, and 9-aminocamptothecin as well as MX. Increased energy-dependent efflux of affected drugs was noted. BCRP is a very efficient transporter of topotecan. Our recent studies, using the monoclonal antibody (mAb) BXP34, revealed that BCRP is located in the plasma membrane of the T8 and MX3 cell lines. Preliminary results of staining of human tumor cells showed low or absent levels of BCRP in a panel of solid tumors and acute myeloid leukemia cells.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2000

Embolization for vertebral metastases of follicular thyroid carcinoma.

The technique of selective embolization has been applied for years in the treatment of vascular anomalies, severe hemorrhage and benign or malignant tumors, notably vertebral metastases of renal cell carcinoma. Because this technique is relatively easy to perform and offers immediate relief of symptoms, it is an attractive option for patients with vertebral metastases of thyroid carcinoma with signs of spinal cord compression. In these patients, other treatment modalities like radioactive iodine, external irradiation, or surgery are more cumbersome or less effective in the short term. We describe four patients with metastasized follicular thyroid carcinoma, presenting with neurological symptoms due to vertebral metastases. All patients had undergone total thyroidectomy, ranging from 1 month to 4 yr before embolization. Embolization was combined with iodine-131 therapy when appropriate. Selective catheterization of the arteries feeding the metastases was performed, followed by infusion of polyvinyl alcohol particles (Ivalon). The procedure was technically successful in all patients without adverse effects. In the patients described, embolization resulted in rapid resolution of neurological symptoms, sometimes within hours. The therapeutic effect lasted from months to years. We conclude that embolization of vertebral metastases of follicular thyroid carcinoma is an attractive palliative therapeutic option that may offer rapid relief of symptoms.

Carcinoma, Papillary, Follicular↗
PubMed2000

Beneficial effects of retinoic acid on extracellular matrix degradation and attachment behaviour in follicular thyroid carcinoma cell lines.

The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on important determinants of metastatic behaviour in FTC: the disengagement of tumour cells from the primary tumour and the degradation of extracellular matrix, focusing on the role of the plasmin activation system and the integrin and E-cadherin families of attachment molecules. Three FTC cell lines were studied: FTC-133, derived from the primary tumour; and FTC-236 and FTC-238, derived from metastases. FTC cell lines were cultured with 0.1, 1 and 10 microM 13-cis-RA or with the solvent DMSO for 1 and 5 days. Extracellular matrix degradation by these cell lines was studied by assessing the 48-h release of radioactivity from (35)S-methionine labelled extracellular matrix proteins synthesised by the MC3T3 cell line coated onto plastic. The involvement of constituents of the plasmin activation system was investigated by semi-quantitative RT-PCR and zymography. Attachment to extracellular matrix was studied by determining the number of adhering FTC cells to extracellular matrix coated onto plastic, 3 h after seeding. The involvement of attachment molecules was studied by RT-PCR with primers for integrin subclasses and E-cadherin and immunofluorescence for E-cadherin. Five days culturing with 10 microM RA reduced the degradation of extracellular matrix significantly in all cell lines: FTC-133 by 35%, FTC-236 by 74% and FTC-238 by 31%. Zymography revealed diminished activity of urokinase type plasminogen activator (uPA) in FTC-236 and FTC-238, but not in FTC-133 cultured with RA. mRNA expression of the uPA receptor was diminished in FTC-236. In the attachment assay, 10 microM RA for 5 days increased the number of adherent cells to extracellular matrix significantly by 91% in FTC-133, 64% in FTC-236 and 87% in FTC-238. No effects of RA on integrin or E-cadherin mRNA expression were observed. Immunofluorescence, however, revealed enhanced organisation of E-cadherin along the cell membrane by RA treatment. In conclusion, the present study demonstrates beneficial effects of RA on important determinants of metastatic behaviour in FTC cell lines, e.g. decreased degradation of extracellular matrix which may in part be explained by effects on the plasmin activation system and enhanced attachment to extracellular matrix. These findings may add to the explanations for beneficial effects of retinoids in thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed2000

Health effects of therapeutic use of 131I in hyperthyroidism.

Since 1942, therapy with radioiodine (Na131I) has gained a major role in the treatment of benign thyroid disorders, notably hyperthyroidism caused by Graves' disease or toxic multinodular goiter. The very large series of patients treated so far offer the opportunity for an assessment of both benign and malignant side effects. Hyperthyroidism is sometimes observed after radioiodine therapy due to radiation induced thyroid hormone or by an immunological mechanism. Despite the numerous attempts to design dosage schedules aiming at euthyroidism, hypothyroidism occurs in the majority of patients throughout life. Transient hypothyroidism may be observed within the first year after therapy and is caused by an immunological mechanism. Radioiodine therapy in Graves' disease may induce or worsen ophthalmopathy, which can be prevented by steroids effectively. Hypoparathyroidism and hyperparathyroidism have been reported after radioiodine therapy but probably do not exceed the normal incidence. Sialitis is commonly observed but mostly in patients treated with radioiodine for thyroid cancer. There are no indications for induction of genetic abnormalities after radioiodine therapy although no definite conclusion can be reached. Much attention has been paid to malignant disease. In very large series, no effects of radioiodine therapy on survival have been observed. Some studies report an increased relative risk for certain types of cancer (notably thyroid cancer, stomach cancer, bladder and kidney cancer or hematological malignancies). However, these observations were not confirmed by other large studies, so that no definite conclusion with respect to risk for certain types of malignant disease can be drawn. However, radioiodine therapy for benign thyroid disorders has generally been considered safe and without major side effects, hypothyroidism being the most frequent one.

Humans↗
PubMed1999

Role of macrophage colony-stimulating factor in the differentiation and expansion of monocytes and dendritic cells from CD34+ progenitor cells.

The present study focused on whether it is possible to expand monocytic cells from CD34+ progenitor cells by using macrophage colony-stimulating factor (M-CSF) in the absence and presence of mast cell growth factor (MGF) and IL-6. It was demonstrated that CD34+ cells differentiate without expansion to functional mature monocytic cells in the presence of M-CSF or combinations of M-CSF plus IL-6 and MGF. A different response pattern was observed for the number of clonogenic cells. The addition of IL-6 or both IL-6 and MGF to M-CSF containing cultures resulted in significant higher numbers of colony-forming unit-macrophage (CFU-M) as tested in clonogenic and 3H-thymidine assays. Furthermore, M-CSF plus both IL-6 and MGF appeared to be the most potent combination to preserve the monocytic precursor in cell suspension culture assays. These results indicate that IL-6 and MGF in conjunction with M-CSF affect CD34+ cells especially at precursor level without distinct effect on the more mature stages. Secondly we studied whether M-CSF is only critical for the monocytic lineage or also affects dendritic cell (DC) development. Indeed, we were able to culture CD83+ DC from CD34+ progenitor cells in the presence of M-CSF in conjunction with TNF-alpha, IL-4, and MGF although their absolute number is almost threefold lower than the number of CD83+ cells yielded from GM-CSF plus TNF-alpha, IL-4, and MGF stimulated CD34+ cells.

Antigens, CD34↗
PubMed1999

Combined hyperlipidemia is associated with increased exercise-induced muscle protein release which is improved by triglyceride-lowering intervention.

Although myopathy is considered an adverse effect of treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates in combined hyperlipidemia, the present study was performed to investigate whether combined hyperlipidemia itself is associated with skeletal muscle pathology and whether lipid-lowering intervention has beneficial effects. To investigate whether combined hyperlipidemia is associated with skeletal muscle pathology, 10 male patients and 15 normolipidemic controls underwent a 45-minute standardized bicycle ergometer test at a load of 2 W/kg lean body mass (parallel study). One- and 8-hour postexercise increments in the plasma level of the muscle proteins creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) were assessed as parameters for (subclinical) skeletal muscle pathology. The 8-hour postexercise increments in CK and Mb and 1-hour postexercise increment in Mb were significantly higher in patients than in controls, thus indicating increased exercise-induced muscle membrane permeability in combined hyperlipidemia. To investigate the effects of lipid-lowering intervention on skeletal muscle in combined hyperlipidemia, 21 subjects with combined hyperlipidemia were randomized double-blindly to receive 6 weeks of treatment with fluvastatin 40 mg/d, gemfibrozil 600 mg twice daily, or combination therapy. All subjects underwent an ergometer test before and after treatment. Gemfibrozil treatment alone reduced the CK increments 8 hours postexercise by 47% and the FABP increments 1 and 8 hours postexercise by 83% and 101%, respectively (all P < .05). Combined treatment reduced Mb increments 1 hour postexercise by 54% and FABP increments 8 hours postexercise by 44% (all P < .05). A highly significant correlation existed between therapy-induced changes in plasma triglycerides and changes in postexercise increments of FABP and Mb. In conclusion, combined hyperlipidemia is associated with an increased exercise-induced release of muscle proteins, which is ameliorated by triglyceride-lowering intervention. As FABP is an indicator for ischemia-induced skeletal muscle pathology, a possible explanation is the impaired muscle blood flow during hypertriglyceridemia, which may be reversed by triglyceride-lowering intervention. The mechanism and clinical relevance of these findings remain to be investigated.

Double-Blind Method↗
PubMed1999

Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: role of the plasmin activation system.

The plasmin activation system plays a key role in extracellular matrix degradation in many malignant tumors. Because no data are available on the involvement of the plasmin activation system in matrix degradation by thyroid carcinoma, the present study was performed using follicular thyroid carcinoma cell lines obtained from a primary tumor (FTC-133) and metastases (FTC-236 and FTC-238) of one patient. Matrix degradation by these cell lines was studied assessing the release of radioactivity from S35-methionine labeled extracellular matrix coated onto plastic. The involvement of constituents of the plasmin activation system as well as matrix metalloproteinases (MMPs), another class of proteolytic enzymes, which can be activated by plasmin, were assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and zymography. In the matrix degradation experiment, S35 release by FTC-133 was significantly higher than FTC-236 and FTC-238. S35 degradation could be inhibited by the plasmin inhibitor aprotinin and by anti-human urokinase-type plasminogen activator (uPA) antibody, indicating the involvement of the plasmin activation system. Matrix degradation could also be inhibited by the MMP inhibitor marimastat, thus demonstrating the involvement of MMPs in matrix degradation by these cell lines. Zymographic assays revealed activity of uPA in all cell lines. However, in contrast with FTC-236 and FTC-238, no plasminogen activator inhibitor (PAI) or PAI1 mRNA were found in FTC-133. Therefore, the differences in PAI activity as observed between the cell lines may originate from differences in PAI1 gene transcription. Differences in PAI1 expression did not affect the attachment of these cell lines to vitronectin. We conclude that the plasmin activation system is involved in extracellular matrix degradation by these metastatic follicular thyroid carcinoma cell lines. Differences in extracellular matrix degradation between the cell lines correspond with differences in PAI1 gene expression, indicating the significance of PAI1 in extracellular matrix degradation by metastatic follicular thyroid carcinoma.

Adenocarcinoma, Follicular↗
PubMed1999

Immune response capacity after human splenic autotransplantation: restoration of response to individual pneumococcal vaccine subtypes.

OBJECTIVE: To evaluate features of general immune function, in particular the restoration of the humoral immune response to pneumococcal capsular polysaccharides, in humans undergoing a spleen autotransplantation after splenectomy because of trauma. SUMMARY BACKGROUND DATA: After splenectomy, patients have an increased risk of overwhelming infection or sepsis involving encapsulated bacteria such as pneumococci. The value of human spleen autotransplantation after splenectomy because of trauma has long been questioned. Mononuclear phagocyte system function appeared to be similar to that in splenectomized persons. The presence of specific antipneumococcal antibodies would allow other parts of the mononuclear phagocyte system, such as those in the liver, to phagocytose opsonized bacteria. METHODS: Ten consecutive patients undergoing splenectomy followed by autotransplantation were compared with the next 14 consecutive patients undergoing splenectomy alone. After a minimum of 6 months, the patients were vaccinated with 23-valent pneumococcal vaccine. Blood samples were taken at the time of vaccination and after 3 and 6 weeks for antipneumococcal capsular polysaccharides IgM and IgG enzyme-linked immunosorbent assay against types 3, 4, 6, 9, 14, and 23. Splenic regrowth was evaluated by scintigraphy. RESULTS: Surprisingly, several of the nonautotransplanted patients showed scintigraphic activity, indicating the presence of either accessory spleens or traumatic seeding (splenosis). Significant antibody titer increases (more than twofold) were found for both IgM and IgG in the autotransplanted patients. Splenectomized-only patients showed no significant increase in Ig levels in patients without splenic regrowth and partial improvement in patients with splenosis/accessory spleens. CONCLUSIONS: Considering this significant antipneumococcal antibody increase, spleen autotransplants can be expected to permit an adequate humoral response to pneumococcal infections and presumably also to other TI-2 antigens, and to protect against overwhelming postsplenectomy infection or sepsis.

Adolescent↗
PubMed1999

Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure.

It was recently shown that naturally occurring Mdr1a mutant fetuses of the CF-1 outbred mouse stock have no placental Mdr1a P-glycoprotein (P-gp) and that this absence is associated with increased sensitivity to avermectin, a teratogenic pesticide. To further define the role of placental drug-transporting P-gp in toxicological protection of the fetus, we used mice with a targeted disruption of the Mdr1a and Mdr1b genes. Mdr1a(+/-)/1b(+/-) females were mated with Mdr1a(+/-)/1b(+/-) males to obtain fetuses of 3 genotypes (Mdr1a(+/+)/1b(+/+), Mdr1a(+/-)/1b(+/-), and Mdr 1a(-/-)/1b(-/-)) in a single mother. Intravenous administration of the P-gp substrate drugs [(3)H]digoxin, [(14)C]saquinavir, or paclitaxel to pregnant dams revealed that 2.4-, 7-, or 16-fold more drug, respectively, entered the Mdr1a(-/-)/1b(-/-) fetuses than entered wild-type fetuses. Furthermore, placental P-gp activity could be completely inhibited by oral administration of the P-gp blockers PSC833 or GG918 to heterozygous mothers. Our findings imply that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds and demonstrate that this P-gp function can be abolished by pharmacological means. The latter principle could be applied clinically to improve pharmacotherapy of the unborn child.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Predictive value of cord blood hematological indices and hemoglobin Barts for the detection of heterozygous alpha-thalassemia-2 in an African-Caribbean population.

BACKGROUND: Cord blood hemoglobin Barts (HbBarts) and hemocytometric indices may be used for classification of newborns into those without alpha-thalassemia-2 (alphaalpha/alphaalpha) and with heterozygous alpha-thalassemia-2 (-alpha(3.7)/alphaalpha). We investigated by logistic regression analysis whether the combination of HbBarts and hemocytometric indices improves classification compared with classification based on a single analyte. METHODS: HbBarts percentages and hemocytometric indices were determined in cord blood of 208 consecutive newborns in Curaçao (Netherlands Antilles). Of these, 157 had alphaalpha/alphaalpha and 51 had -alpha(3.7)/alphaalpha, as established by DNA analysis. RESULTS: Between-group differences were significant for erythrocytes, mean cell volume, mean cell hemoglobin (MCH), mean cell hemoglobin concentration, platelets, hemoglobin F(0) (HbF(0)), and HbBarts. The Logit equation of the logistic regression model, using MCH (pg) and HbBarts (%), was: 42.7164 + 5.7916(HbBarts) - 1.3110(MCH). A sensitivity of 100% was reached at a Logit value of -3.70. The corresponding specificity was 62.2%, and the predictive value of a positive test (PV+) was 46.3% (95% confidence interval, 37.0-55.7%). The relative information gains were as follows: 88% for the HbBarts-MCH combination, 26% for MCH (not significant), and 0% for HbBarts compared with the 24.6% -alpha(3.7)/alphaalpha prevalence. CONCLUSION: Combined use of cord blood HbBarts and MCH improves classification compared with classification based on single hemocytometric indices.

Black People↗
PubMed1998

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

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 amines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level.

1. In the present study it was tested whether known P-glycoprotein (P-gp) substrates/MDR reversal agents interact with small (type 1) and bulky (type 2) cationic drugs at the level of biliary excretion in the rat isolated perfused liver model (IPRL). The studies were performed with model compounds tri-n-butylmethylammonium (TBuMA) (a relatively small type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cation) and the classical P-gp substrate doxorubicin (Dox). 2. Inhibitors were given in a 4 fold molar excess to the substrate studied. To minimize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administered dose of the model compounds had been removed from the perfusate and taken up by the liver. 3. We found a mutual interaction between TBuMA and procainamidethobromide (PAEB), both type 1 cationic compounds during biliary excretion. Interestingly, type 2 compounds, such as rocuronium, clearly inhibited type 1 cationic drugs as well as Dox secretion into bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only moderately inhibited Dox biliary excretion. Dox did not inhibit the biliary excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls. 4. MDR substrates/reversal agents like verapamil, quinine, quinidine and vinblastine strongly reduced both type 1 and type 2 organic cation excretion into bile. Dox secretion into bile was also profoundly reduced by these drugs, vinblastine being the most potent inhibitor in general. 5. The lack of mutual inhibition observed in some combinations of substrates may indicate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transport systems with separate substrate specificities may be involved in the biliary excretion of amphiphilic drugs. Furthermore, the present study revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory activity on the biliary excretion of the model drugs investigated. 6. Our data are compatible with a potential involvement of P-glycoprotein in the hepatobiliary excretion of doxorubicin as well as of some type 1 and type 2 organic cations. Furthermore we postulate that the hydrophobic properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P-glycoprotein and/or other potential cationic drug carrier proteins in the canalicular membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗