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PubMed2002

Loss of multidrug resistance protein 1 expression and folate efflux activity results in a highly concentrative folate transport in human leukemia cells.

We studied the molecular basis of the up to 46-fold increased accumulation of folates and methotrexate (MTX) in human leukemia CEM-7A cells established by gradual deprivation of leucovorin (LCV). CEM-7A cells consequently exhibited 10- and 68-fold decreased LCV and folic acid growth requirements and 23-25-fold hypersensitivity to MTX and edatrexate. Although CEM-7A cells displayed a 74-86-fold increase in the reduced folate carrier (RFC)-mediated influx of LCV and MTX, RFC overexpression per se cannot induce a prominently increased folate/MTX accumulation because RFC functions as a nonconcentrative anion exchanger. We therefore explored the possibility that folate efflux activity mediated by members of the multidrug resistance protein (MRP) family was impaired in CEM-7A cells. Parental CEM cells expressed substantial levels of MRP1, MRP4, poor MRP5 levels, whereas MRP2, MRP3 and breast cancer resistance protein were undetectable. In contrast, CEM-7A cells lost 95% of MRP1 levels while retaining parental expression of MRP4 and MRP5. Consequently, CEM-7A cells displayed a 5-fold decrease in the [(3)H]folic acid efflux rate constant, which was identical to that obtained with parental CEM cells, when their folic acid efflux was blocked (78%) with probenecid. Furthermore, when compared with parental CEM, CEM-7A cells accumulated 2-fold more calcein fluorescence. Treatment of parental cells with the MRP1 efflux inhibitors MK571 and probenecid resulted in a 60-100% increase in calcein fluorescence. In contrast, these inhibitors failed to alter the calcein fluorescence in CEM-7A cells, which markedly lost MRP1 expression. Replenishment of LCV in the growth medium of CEM-7A cells resulted in resumption of normal MRP1 expression. These results establish for the first time that MRP1 is the primary folate efflux route in CEM leukemia cells and that the loss of folate efflux activity is an efficient means of markedly augmenting cellular folate pools. These findings suggest a functional role for MRP1 in the maintenance of cellular folate homeostasis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist.

Acute Kidney Injury↗
PubMedDate not supplied

Effects of drugs which influence renal transport systems on the urinary excretion of the beta 2-adrenoceptor agonist clenbuterol and the anabolic steroids ethinylestradiol and methyltestosterone.

The aim of this study was to determine whether the illegal application of clenbuterol, ethinylestradiol and methyltestosterone in cattle as growth promoters can be concealed by co-treatment with drugs that affect urinary excretion. Six male veal calves were fed with 0.8 micrograms clenbuterol kg-1 of body weight (BW), 3.5 micrograms ethinylestradiol kg-1 BW and 35 micrograms methyltestosterone kg-1 BW together twice daily for 28 days. At the eighth day of clenbuterol, ethinylestradiol and methyltestosterone treatment each calf was additionally fed either with probenecid, para-aminohippuric acid, trimethoprim, famotidine or cimetidine at three different doses which were increased in weekly intervals. During the treatment 24 h-urine and blood samples (once daily) were obtained and analysed for clenbuterol, ethinylestradiol and methyltestosterone by specific enzyme immunoassay. By high performance liquid chromatography/enzyme immunoassay it was determined whether these drugs or their metabolites interfered with the immunological detection of the growth promoters. Clenbuterol, ethinylestradiol and methyltestosterone could be detected in plasma and urine throughout the whole experiment. Co-treatment with probenecid led to a five-fold reduction in urinary excretion of ethinylestradiol and co-treatment with trimethoprim led to a three-fold reduction in urinary excretion of clenbuterol. None of the drugs reduced urinary excretion of the growth promoters to concentrations below the limit of detection. The detection of these three growth promoters in urine samples from calves which were co-treated with the drugs tested in this study can thus not be prevented.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Treatment of uncomplicated gonococcal urethritis with cefoxitin: comparison with penicillin.

Cefoxitin is a semisynthetic cephamycin with good in vitro activity against Neisseria gonorrhoeae. In a controlled clinical trial, 143 men with uncomplicated gonococcal urethritis received either cefoxitin (2.0 g intramuscularly [im] with 1.0 g of oral probenecid) or aqueous procaine penicillin G (4.8 x 10(6) units im with 1.0 g of oral probenecid). Of the 117 patients who returned for follow-up on days 3-13 after treatment, only 1.8% in the group given cefoxitin and 3.6% in the group given penicillin were not cured. The incidence of pain at the site of injection and rates of adverse reactions were similar for both groups. No hematologic, renal, or hepatic toxicity could be ascribed to either treatment regimen. Although none of the infections were due to beta-lactamase-producing gonococci, the results provide a basis for additional studies of the efficacy of cefoxitin in treatment of infections due to penicillinase-producing N. gonorrhoeae.

Cefoxitin↗
PubMed1992

Cumene hydroperoxide induced changes in calcium homeostasis in cultured neonatal rat heart cells.

OBJECTIVE: The relationship between oxidative stress induced cell necrosis and perturbation of intracellular calcium homeostasis was investigated in cultured myocytes. METHODS: Cultured neonatal rat heart cells were loaded with fura-2 AM to measure cytosolic free calcium ([Ca2+]i). Probenecid, an inhibitor of organic anion transport, was present during the experiment to reduce efflux of fura-2 from the cytoplasm. Cells were exposed to cumene hydroperoxide, a toxic organic hydroperoxide that is known to induce oxidative stress in myocytes. The efficacy of the protective agents Trolox C (a vitamin E analogue) and chlorpromazine (a phospholipase inhibitor) on cumene hydroperoxide induced cell injury was determined. RESULTS: [Ca2+]i in control cells was constant (60 nM) during an incubation time of 45 min. Probenecid did not affect [Ca2+]i levels or cell viability under the experimental conditions. Cumene hydroperoxide caused a sustained rise in [Ca2+]i starting after 5-10 min, to a level of 1300 nM at 45 min. After 20-25 min the viability of the heart cells started to decline and after 45 min 44% of the cells were irreversibly injured. The loss of cell viability was expressed as percentage decrease of the fluorescence at 360 nm (the calcium independent wavelength), since the percent release of cellular alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) activity equalled the percent decrease of the fluorescence at 360 nm. Trolox C and chlorpromazine almost completely prevented the cumene hydroperoxide induced alpha-HBDH release. The [Ca2+]i of myocytes incubated with cumene hydroperoxide in combination with Trolox C rose to 1000 nM without affecting cell viability. The cumene hydroperoxide induced rise in [Ca2+]i was markedly reduced by chlorpromazine (at t = 45 min, [Ca2+]i = 360 nM). Addition of Trolox C to untreated cells did not influence [Ca2+]i, whereas chlorpromazine alone induced a slight increase of [Ca2+]i up to 360 nM with complete preservation of cell viability. CONCLUSIONS: Trolox C and chlorpromazine are very effective inhibitors of cumene hydroperoxide induced perturbation of calcium homeostasis and subsequent cell death. A role for peroxidation of membrane phospholipids and activation of calcium dependent phospholipase in the cascade of events leading to irreversible injury is suggested.

Animals↗
PubMed1989

Pharmacokinetics of FCE 22101 in man following different modes of administration.

Twelve healthy volunteers received single iv doses of either 500 and 1000 mg or 750 and 1500 mg of the sodium salt of FCE 22101; in addition, five of the volunteers received a further dose of 2000 mg. In the second part of the study, 11 of the volunteers received 1000 mg doses of FCE 22101 in a four-way randomized fashion by iv bolus (1000 mg, with and without probenecid), im injection (1000 mg plus lignocaine) and a continuous infusion (280 mg/h) to steady state. All doses were well tolerated by the volunteers with no serious side effects and no significant haematological or biochemical changes following drug administration. Plasma and urine concentrations of FCE 22101, and in the cross-over study also its open ring metabolites P1 and P2, were determined by HPLC. Good linearity was observed between the peak plasma levels or AUC and the dose given. Plasma concentrations were fitted to a two-compartment model and the mean pharmacokinetic parameters determined after iv bolus were: Cmax 117 mg/l, T1/2 beta 36 min, Vss 181, AUC 2179 mg/min/l with urinary recoveries of FCE 22101 37%, P1 36% and P2 6%. With probenecid the values were Cmax 116 mg/l, T1/2 beta 47 min, Vss 141, AUC 4540 mg/min/l and urinary recoveries of FCE 22101 20%, P1 40% and P2 7%. Following im injection the mean values were Cmax 15 mg/l, Tmax 30 min, T1/2abs 14 min, T1/2 beta 61 min, AUC 2117 mg/min/l and urinary recoveries of FCE 22101 33%, P1 37% and P2 6%. At steady state during continuous infusion, mean values were Css 12.7 mg/l, Vss 131 and T1/2 beta after steady state was 22 min. Although urinary recoveries varied widely between volunteers there was a tendency towards consistency of recovery within individual volunteers. We conclude that FCE 22101 is a well tolerated penem with pharmacokinetic properties broadly similar to those of other penem and carbapenem antibiotics.

Adolescent↗
PubMed2002

Glial cells express multiple ATP binding cassette proteins which are involved in ATP release.

Rat brain astrocyte and microglia cultures express different members of ATP-binding-cassette (ABC) proteins. RT-PCR analysis showed that astrocytes are equipped with P-glycoprotein (mdr1a, mdr1b), multidrug resistance-associated-protein (mrp1, mrp4, mrp5) and cystic fibrosis transmembrane conductance regulator (CFTR). No transcripts for mrp5 and CFTR were detected in microglia. The ABC protein functional activities are shown by the following results: (i) cyclosporin A (50 microM), verapamil (50 microM), probenecid (1 mM) or sulfinpyrazone (2 mM) enhanced [3H]vincristine accumulation; (ii) cyclosporin A or verapamil but not probenecid or sulfinpyrazone enhanced [3H]digoxin accumulation; (iii) glibenclamide (100 microM) inhibited 36Cl efflux from astrocytes. ATP release from glial cells was inhibited by the pretreatment with ABC protein inhibitors indicating that ABC proteins are involved in nucleotide efflux from glial cells which represent the main source of cerebral extracellular purines.

ATP Binding Cassette Transporter, Subfamily B↗
PubMedDate not supplied

One gram of cefoxitin cures uncomplicated gonococcal urethritis caused by penicillinase-producing Neisseria gonorrhoeae (PPNG).

Therapy of disease caused by penicillinase-producing Neisseria gonorrhoeae with lower-than-standard doses of cefoxitin was evaluated. A pilot study showed that doses of greater than or equal to 1 g were adequate, whereas 500-mg doses consistently failed. After the pilot study, 89 men with gonorrhea were treated with 1 g of cefoxitin given intramuscularly plus 1 g of probenecid given orally. Of the 89 men, 86 were cured. Sixty per cent were infected with penicillin-resistant strains of N. gonorrhoeae. The three men who were culture-positive on follow-up had been sexually reexposed, whereas none of those with negative cultures had had reexposure. These clinical results indicate that a treatment regimen of 1 g of parenteral cefoxitin plus 1 g of oral probenecid appears to be as effective as the standard 2-g dose. Regimens using doses lower than 1 g are ineffective.

Adolescent↗
PubMed1999

Loss of Tonoplast Integrity Programmed in Tracheary Element Differentiation.

A tracheary element (TE) is a typical example of a cell type that undergoes programmed cell death in the developmental processes of vascular plants. The loss of the selective permeability of the tonoplast, which corresponds to tonoplast disintegration, occurred after the cells commenced secondary wall thickening and played a pivotal role in the programmed cell death of TEs in a zinnia (Zinnia elegans L.) cell culture. A search for events specifically associated with the TE vacuole provided an important clue to the understanding of the cell death mechanism. The transport of fluorescein, a fluorescent organic anion, across the tonoplast declined drastically in differentiating TEs. The capacity of the vacuole to accumulate the probe was also impaired. Treatment with probenecid, an inhibitor of organic anion transport, caused rapid cell death of TEs and led to the ultimate disruption of the vacuole even in other types of cultured cells. These changes in vacuolar properties during TE development were suppressed by cycloheximide. Specific mRNA accumulation in cells cultured in a TE differentiation-inductive condition was abolished by probenecid. These results suggest that a change in vacuolar membrane permeability promotes programmed cell death in TEs.

Journal Article↗
PubMed1984

Accumulation of pantothenic acid by the isolated choroid plexus and brain slices in vitro.

In vitro, the transport of [14C]pantothenic acid into and from the isolated rabbit choroid plexus, an anatomical locus of the blood-CSF barrier, and brain slices was studied. The choroid plexus accumulated [14C]pantothenic acid from the medium against a concentration gradient, although at low concentrations (less than 1 microM) there was substantial intracellular phosphorylation and binding of the [14C]pantothenic acid. The saturable accumulation process in choroid plexus was inhibited by probenecid and caproic acid but not by nicotinic acid or by weak bases. The accumulation process was markedly inhibited by N-ethylmaleimide, poly-L-lysine (which blocks sodium transport), and low temperatures. [14C]Pantothenic acid was readily released from choroid plexus by a temperature-dependent process. Brain slices also accumulated and, at low concentrations, phosphorylated [14C]pantothenic acid from the medium by a temperature-, probenecid-, and N-ethylmaleimide-sensitive saturable process. However, unlike choroid plexus, brain slices did not concentrate free pantothenic acid and [14C]pantothenic acid accumulation was not sensitive to poly-L-lysine. [14C]Pantothenic acid was readily released from brain slices by a temperature-sensitive process. These results are consistent with the view that [14C]pantothenic acid enters the isolated choroid plexus and brain slices by active transport and facilitated diffusion, respectively.

Animals↗
PubMed1993

Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.

1. In this study, a number of structurally different N-acetyl-L-gamma-glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats. 2. All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para-nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid-sensitive carrier. The prodrug of 4'-aminoantipyrine (agAAP) was not accumulated by a probenecid- or buthionine sulphoximine-sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro. 3. agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only. 4. The factors which determine the selectivity of N-acetyl-L-gamma-glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver. It is concluded that this prodrug approach offers the possibility of delivering drugs selectively to the kidney, but also that it is not universally applicable.

Ampyrone↗
PubMed1988

Treatment of erythema chronicum migrans of Lyme disease.

Between June 1981 and July 1987 the efficacy of antibiotic treatment of 215 patients with erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for retreatment and the prevention of the late manifestations of Lyme disease. The principal antibiotics utilized to treat 161 patients through 1986 were varying doses of tetracycline, or penicillin alone or in combination with probenecid. Two of 80 patients with a minor form of the illness and 17 of 81 patients with a major form of the illness required retreatment. There were four patients who did not respond to retreatment with their original medication. A 15- to 30-day course of amoxicillin (500 mg q.i.d.) and probenecid (500 mg q.i.d.) or doxycycline (100 mg t.i.d.), and on three occasions ceftriaxone (2-4 g/day i.v.), were used to treat 54 patients in 1987. Although it is too early to judge the efficacy of treatment in these patients, increases in the incidence of Herxheimer reactions and drug eruptions were observed. Strict compliance with treatment protocols and the possibility of reactions to medications should be thoroughly discussed with patients.

Adult↗
PubMed1995

Comparative convulsant potencies of two carbapenem derivatives in C57 and DBA/2 mice.

The behavioural and convulsant effects of imipenem and meropenem were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizure, and in C57 mice, a strain not prone to seizure. DBA/2 mice were more susceptible than C57 mice to seizures induced by imipenem-cilastatin or meropenem. Imipenem was also 1.9 times more potent than meropenem in inducing clonus in DBA/2 mice. To investigate the possibility that the seizure-inducing activity of imipenem might be due to a probenecid-like effect of cilastatin, animals were treated with imipenem alone. No significant differences were observed between imipenem-cilastatin and imipenem-treated animals. Thus, it is reasonable to exclude a probenecid-like effect of cilastatin. Although the main mechanism for seizure-like activity of imipenem cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of imipenem from the CNS may be postulated. Cilastatin did not induce seizures. In addition, meropenem, a compound structurally related to imipenem, showed weak or no convulsant effects.

Animals↗
PubMed1981

Mapping, in the rat central nervous system, of morphine-induced changes in turnover of 5-hydroxytryptamine.

1. It is known that the full clinical effect of morphine is not seen if those neurones of the central nervous system which contain 5-hydroxytryptamine (5-HT) have been inactivated. Morphine increases 5-HT turnover in brain and cord, and the present work is an attempt at mapping the sites at which turnover is accelerated. 2. The degree of interaction at various sites of the C.N.S. was measured by the increment in the content of 5-hydroxyindol-3-yl acetic acid (5-HIAA) elicited by morphine in rats pre-treated with probenecid. The effect was produced by as little as 3.5 mg morphine hydrochloride/kg; for the sake of convenience this dose was doubled in most experiments. Pre-treatment with probenecid was not necessary for the effect, but a minimum interval of 90 min between injection of morphine and analysis of the brain was essential. 3. Morphine did not act indiscriminately on all 5-HT neurons, as seen by the fact that the increment in 5-HIAA formation was independent of the density of 5-HT neurones in the tissue. Nor was there any relation between basal 5-HT turnover of a region and the size of its response to morphine. 4. Highly reactive sites were found in dorsal cord, medulla, superior colliculi, substantia nigra, thalamus, hypothalamus, amygdala and striatum. Cortical areas were less responsive, but with large differences among themselves. Hippocampus, central grey, olfactory bulb, cerebellum and white matter had lower or negligible increases in 5-HT turnover. There was no increase in the turnover of the (non-neural) 5-HT of the pineal gland. 5. The relation of the reactive sites to their content in endogenous opioids and to the probable localization of the pharmacological actions of morphine is discussed.

Animals↗
PubMed2005

Functional characterization of human monocarboxylate transporter 6 (SLC16A5).

Human monocarboxylate transporter 6 (MCT6) has recently been isolated, and its tissue distribution has been established at the mRNA level, but its functional properties remain unknown. The aim of this study is to investigate the transport properties of MCT6. When expressed in Xenopus laevis oocytes, MCT6 transported [3H]bumetanide in a pH- and membrane potential-sensitive but not proton gradient-dependent manner, with the K(t) value of 84 microM. Furthermore, MCT6 transported various drugs such as probenecid and nateglinide. Neither [14C]L-lactic acid nor [3H]L-tryptophan, typical substrates of other MCT isoforms, was transported by MCT6. Four loop diuretics, i.e., furosemide, piretanide, azosemide, and torasemide, thiazides, probenecid, glibenclamide, and nateglinide inhibited the MCT6-mediated uptake of [3H]bumetanide. In contrast, short-chain carboxylic acids, such as L-lactic acid and succinic acid did not inhibit the MCT6-mediated uptake of bumetanide. These results suggest that the substrate specificity of MCT6 is distinct from those of other MCTs. Bumetanide would be a good tool for investigating the functional properties of MCT6. It is probable that MCT6 is involved in the disposition of various drugs, including bumetanide.

Animals↗
PubMed2003

Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity.

The blood-brain barrier (BBB) is a physical and metabolic barrier between the brain and the systemic circulation, which functions to protect the brain from circulating drugs, toxins, and xenobiotics. ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1), which are found in the apical (luminal) membranes of brain capillary endothelial cells, are thought to play an important role in BBB function by limiting drug penetration into the brain. More recently, the multidrug resistance protein MRP2 (ABCC2) has been found in the luminal surface of brain capillary endothelium of different species, including humans. In endothelial cells from patients with drug-resistant epilepsy, MRP2 was shown to be overexpressed, indicating that it may be critically involved in multidrug resistance of such patients. However, the role of MRP2 in drug disposition into the brain is defined poorly. Herein, we used different strategies to study the contribution of MRP2 to BBB function. First, the MRP inhibitor probenecid was shown to increase extracellular brain levels of the major antiepileptic drug phenytoin in rats, indicating that phenytoin is a substrate of MRP2 in the BBB. This was substantiated by using MRP2-deficient TR- rats, in which extracellular brain levels of phenytoin were significantly higher compared with the normal background strain. In the kindling model of epilepsy, coadministration of probenecid significantly increased the anticonvulsant activity of phenytoin. In kindled MRP2-deficient rats, phenytoin exerted a markedly higher anticonvulsant activity than in normal rats. These data indicate that MRP2 substantially contributes to BBB function.

Animals↗
PubMed2005

Quantitative in vivo microdialysis study on the influence of multidrug transporters on the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoamines as pharmacodynamic markers for the anticonvulsant activity.

Various antiepileptic drugs were shown to be substrates for multidrug transporters at the level of the blood-brain barrier. These ATP-dependent efflux pumps actively limit brain accumulation of xenobiotics and drugs. Intrahippocampal oxcarbazepine perfusion in rat was previously shown to exert anticonvulsant effects associated with increases in extracellular dopamine and serotonin levels. In contrast, preliminary studies in our laboratory revealed that no anticonvulsant or monoaminergic effects could be obtained after systemic oxcarbazepine administration. The present in vivo microdialysis study was conducted to investigate the impact of the transport kinetics of oxcarbazepine across the blood-brain barrier on the observed treatment refractoriness. More precisely, the influence of intrahippocampal perfusion of verapamil, a P-glycoprotein inhibitor, and probenecid, a multidrug resistance protein inhibitor, on the blood-brain barrier passage and anticonvulsant properties of oxcarbazepine were investigated in the focal pilocarpine model for limbic seizures. Simultaneously, the effects on hippocampal monoamines were studied as pharmacodynamic markers for the anticonvulsant activity. Although systemic oxcarbazepine administration alone failed in preventing the animals from developing seizures, coadministration with verapamil or probenecid offered complete protection. Concomitantly, significant increases in extracellular hippocampal dopamine and serotonin levels were observed within our previously defined anticonvulsant monoamine range. The present data indicate that oxcarbazepine is a substrate for multidrug transporters at the blood-brain barrier. Coadministration with multidrug transporter inhibitors significantly potentiates the anticonvulsant activity of oxcarbazepine and offers opportunities for treatment of pharmacoresistant epilepsy.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1.

Nephrotoxicity is the dose-limiting clinical adverse effect of cidofovir and adefovir, two potent antiviral therapeutics. Because renal uptake likely plays a role in the etiology of cidofovir- and adefovir-associated nephrotoxicity, we attempted to identify a renal transporter capable of interacting with these therapeutics. A cDNA clone was isolated from a human renal library and designated human organic anion transporter 1 (hOAT1). Northern analysis detected a specific 2.5-kilobase pair hOAT1 transcript only in human kidney. However, reverse transcription-polymerase chain reaction revealed hOAT1 expression in human brain and skeletal muscle, as well. Immunoblot analysis of human kidney cortex demonstrated that hOAT1 is an 80- to 90-kilodalton heterogeneous protein modified by abundant N-glycosylation. Xenopus laevis oocytes expressing hOAT1 supported probenecid-sensitive uptake of [(3)H]p-aminohippurate (K(m) = 4 microM), which was trans-stimulated in oocytes preloaded with glutarate. Importantly, both hOAT1 and rat renal organic anion transporter 1 (rROAT1) mediated saturable, probenecid-sensitive uptake of cidofovir, adefovir, and other nucleoside phosphonate antivirals. The affinity of hOAT1 toward cidofovir and adefovir (K(m) = 46 and 30 microM, respectively) was 5- to 9-fold higher compared with rROAT1 (K(m) = 238 and 270 microM, respectively). These data indicate that hOAT1 may significantly contribute to the accumulation of cidofovir and adefovir in renal proximal tubules and, thus, play an active role in the mechanism of nephrotoxicity associated with these antiviral therapeutics.

Adenine↗