Coadministration Of Probenecid Research Articles

Effects of probenecid on the pharmacokinetics of mizoribine and co-administration of the two drugs in patients with nephrotic syndrome

Probenecid (PRB) is an agent that reduces the systemic level of uric acid, and has the ability to inhibit the renal tubular secretion of agents that are co-administered with it. In this study, we evaluated the effects of PRB co-administered with mizoribine (MZR) on the pharmacokinetics (PK) of MZR in 12 patients with nephrotic syndrome. The elimination rate constant (kel) was used as an indicator of changes in the PK of MZR when the secretion of MZR was inhibited by co-administration of PRB, in order to determine the extent to which MZR was influenced by PRB. In 4 of the 12 patients studied, kel decreased and the biological half-life (t1/2) of MZR was prolonged when co-administered with PRB, in comparison with the values when MZR was used alone, thus revealing that the PK of MZR was influenced by PRB. Co-administration of PRB with MZR appears to be effective in prolonging the biological half-life of MZR and enhancing its effect in patients with nephrotic syndrome, although further studies will be required to determine the optimal dosage of PRB and renoprotective effects.

Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro

Akebia saponin D is a typical bioactive triterpenoid saponin isolated the rhizome of Dipsacus asper Wall. Our previous studies demonstrated that the oral bioavailability of akebia saponin D was very low, but the underlying mechanisms remained unknown. The present study aims to investigate the intestinal absorptive characteristics of akebia saponin D as well as the absorptive transport behavior influenced by co-administration of three absorption-enhancing agents and three efflux protein inhibitors using an in vitro everted gut sac method and an in situ intestinal perfusion model. The results showed that akebia saponin D had a quite limited intestinal permeability, and there was a non-linear increase in transepithelial transportation with increasing concentrations of akebia saponin D. The absorption of akebia saponin D was intestinal segment selective and the small intestine was the best absorptive site. Among three absorption promoters, borneol could significantly improve the permeability of akebia saponin D across ileum, while Tween-80 and DMSO had almost no absorption-enhancing effect. In addition, verapamil, probenecid and pantoprazole in the perfusates were used in this study as modulators of transporters such as P-glycoprotein, MRPs and BCRP in the intestinal mucosa, respectively. The results exhibited that the ileal permeability of akebia saponin D was markedly elevated by the co-administration of probenecid, indicating that akebia saponin D may be likely a substrate of MRPs. The above-mentioned results suggest that akebia saponin D has a poor intestinal absorption not only due to its poor transepithelial permeability but also owing to the contribution of efflux transporters such as MRPs in the intestine.

The effects of drug transporter inhibitors on the pharmacokinetics and tissue distribution of methotrexate in normal and tumor-bearing mice: a microdialysis study

To examine methotrexate (MTX) tumor delivery in a mouse model using an in vivo microdialysis technique and to characterize the impact of prior administration of the known transporter inhibitors probenecid and cyclosporine (CsA), alone and in combination, on plasma and tumor pharmacokinetics of MTX. Different groups of mice were used to evaluate the plasma pharmacokinetics of MTX and the impact of prior administration of probenecid and/or CsA on the plasma pharmacokinetics. Xenografted nude mice were used for microdialysis experiments to measure the subcutaneous (SC), peri- and intratumoral pharmacokinetics of MTX without and with coadministration of probenecid, CsA, and both probenecid and CsA. The SC dialysates in pre-treated groups demonstrated a delayed disappearance and an enhanced MTX exposure. Similar effects were observed in the tumor peripheral zone. However, this increase was less pronounced. The central tumor findings demonstrated that CsA had a more significant impact on the enhancement of MTX exposure. Probenecid did not increase the exposure of MTX inside the tumor, but caused a longer half-life of central MTX. This study revealed significant differences in the relative estimated PK parameters of the plasma, SC, peri-, and intratumoral zones. Additionally, this study demonstrated that the coadministration of MTX with CsA can enhance the intratumoral exposure levels of the drug, whereas coadministration of MTX with probenecid alone, or with a combination of probenecid and CsA, increases intratumoral half-life.

Pharmacokinetics of High-Dose Oseltamivir in Healthy Volunteers

The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.

The Inhibition of Human Multidrug and Toxin Extrusion 1 Is Involved in the Drug-Drug Interaction Caused by Cimetidine

Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.

Probenecid, but Not Cystic Fibrosis, Alters the Total and Renal Clearance of Fexofenadine

This study aims to evaluate renal P-glycoprotein (P-gp) activity in patients with cystic fibrosis. P-gp efflux activity in peripheral T cells was measured by flow cytometry in 10 cystic fibrosis and 15 healthy volunteers. Eight cystic fibrosis patients and 8 healthy volunteers were recruited into a crossover pharmacokinetic study in which participants received 180 mg fexofenadine with or without 1 g probenecid twice a day. Genotyping was performed for ABCB1 C1236T, G2677T, and C3435T. P-gp efflux activity in peripheral T cells was not significantly different between cystic fibrosis patients and healthy volunteers. No difference in fexofenadine pharmacokinetic parameters was observed between cystic fibrosis patients and healthy volunteers when fexofenadine was administered with or without probenecid. Coadministration of probenecid significantly increased fexofenadine AUC and decreased the cumulative urinary excretion, total body clearance, and renal clearance. ABCB1 3435 C/T carriers showed increased basal P-gp activity in CD4+ and CD8+ T cells, increased R123-induced efflux activity in CD4+ T cell, and decreased fexofenadine AUC. Fexofenadine disposition and P-gp efflux activity in peripheral T cells was similar between cystic fibrosis patients and healthy volunteers. Probenecid administration significantly reduced the total body and renal clearance of fexofenadine. ABCB1 3435 C/T was associated with an elevated efflux activity compared with C/C subjects.

Pharmacokinetic and Pharmacodynamic Interaction between Allopurinol and Probenecid??in Healthy Subjects

Combination therapy with allopurinol and probenecid is used to treat tophaceous gout in patients who do not respond sufficiently to allopurinol alone. However, the potential interaction between these drugs has not been systematically investigated. The objective of this study was to investigate the pharmacokinetics and hypouricaemic effect of oxypurinol (the active metabolite of allopurinol) and probenecid when administered alone and in combination in healthy subjects. An open-label, randomized, three-way crossover clinical trial was conducted in 12 healthy adults. Subjects were randomized to receive treatment for 7 days with allopurinol (150 mg twice daily), probenecid (500 mg twice daily) or combination therapy with both drugs, with a 7-day washout period between treatments. Venous blood samples were collected predose (at 0 hours) and 1, 2, 3, 4, 6, 8, 10 and 12 hours after dosage for determination of oxypurinol and/or probenecid concentrations. Plasma and urinary urate concentrations were determined on each study day and at the end of each washout period. Pharmacokinetic and pharmacodynamic parameters were analysed using two-way ANOVA. Coadministration of allopurinol and probenecid significantly reduced average steady-state plasma oxypurinol concentrations (mean+/-SD: allopurinol alone 9.7+/-2.1 mg/L vs combination 5.1+/-1.0 mg/L, p<0.001). Probenecid concentrations were unaffected. Plasma urate concentrations decreased (p<0.01) during allopurinol therapy (0.16+/-0.05 mmol/L), probenecid therapy (0.13+/-0.02 mmol/L) and combination therapy (0.09+/-0.02 mmol/L) compared with baseline (0.30+/-0.05 mmol/L). Coadministration of allopurinol and probenecid to healthy subjects had a greater hypouricaemic effect than either allopurinol or probenecid alone, despite a reduction in plasma oxypurinol concentrations when the drugs were taken concomitantly.

Brain‐to‐blood elimination of 24S‐hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood–brain barrier

24S-Hydroxycholesterol (24S-OH-chol), a major cerebral cholesterol metabolite, is an endogenous ligand for the liver X receptor and is a potential stimulant of cholesterol release from glial cells. The elimination mechanism of 24S-OH-chol from the brain is one of the key issues for understanding cerebral cholesterol homeostasis. The purpose of the present study was to clarify the molecular mechanism of the elimination process of 24S-OH-chol across the blood-brain barrier (BBB). After an intracerebral injection in rats, [(3)H]24S-OH-chol was eliminated from the brain and the radioactivity derived from [(3)H]24S-OH-chol was detected in the plasma, while [(3)H]cholesterol was not significantly eliminated from the brain. Co-administration of unlabeled 24S-OH-chol significantly inhibited the [(3)H]24S-OH-chol elimination, while no inhibitory effect was seen at the same concentration of cholesterol. The [(3)H]24S-OH-chol elimination was inhibited by co-administration of probenecid, but not by benzylpenicillin. Pre-administration of digoxin completely inhibited the elimination. Xenopus laevis oocytes expressing rat oatp2 exhibited significant transport of [(3)H]24S-OH-chol, and this was inhibited by unlabeled 24S-OH-chol and digoxin, indicating that rat oatp2 transports 24S-OH-chol. These results are the first direct demonstration that 24S-OH-chol undergoes elimination from the brain to blood across the BBB via a carrier-mediated process, which involves oatp2 expressed at the BBB in rats.

Probenecid with Oseltamivir for Human Influenza A (H5N1) Virus Infection?

To the Editor: Probenecid is an inexpensive medication that was widely used when penicillin was in short supply. Owing to the current easy access to abundant supplies of penicillin, this approach is primarily of historical interest. In light of the limited supply of oseltamivir, however, it may be time to revisit the use of probenecid as adjunctive therapy for human influenza A (H5N1) virus infection. Coadministration of oseltamivir and probenecid has resulted in a reduction in the clearance of oseltamivir by approximately 50 percent and a corresponding doubling of the plasma levels of oseltamivir.1 Therefore, part of the planning for . . .

Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

흰쥐에서 프로베네시드가 프라노푸로펜의 약동학적 거동에 미치는 영향

The purpose of this study was to investigate the effect of probencid on the pharmacokinetics of oral pranoprofen in rats. Pranoprofen (5 mg/kg) was coadministered with 5, 10 or 20 mg/kg of probenecid orally. Coadministration of probenecid significantly altered the pharmacokinetics of pranoprofen at 10 and 20 mg/kg. Compared with the control group, probenecid significantly (p, the peak concentrations and accordingly the area under the plasma concentration-time curve (AUC) of pranoprofen at the dose level of 10 mg/kg and 20 mg/kg of probenecid. The relative bioavailability (RB%) of pranoprofen was 1.64- to 1.82- fold increased. Furthermore, 10 and 20 mg/kg probenecid induced the decreased elimination constants and the prolonged half-lives of pranoprofen with significance (p

Coadministration of probenecid decreases the AUC of carbamazepine, but increases the AUC of its active metabolite carbamazepine 10,11-epoxide,

Coadministration of probenecid decreases the AUC of carbamazepine, but increases the AUC of its active metabolite carbamazepine 10,11-epoxide,

Coadministration of probenecid decreases the AUC of carbamazepine, but increases the AUC of its active metabolite carbamazepine 10,11-epoxide,

Coadministration of probenecid decreases the AUC of carbamazepine, but increases the AUC of its active metabolite carbamazepine 10,11-epoxide,

MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid

ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor.

Mice Lacking α-Synuclein have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration

The functional role of α-synuclein in the pathogenesis of Parkinson’s disease (PD) is not fully understood. Systemic exposure of α-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how α-synuclein may mediate cell death in a common murine model of PD. To this end, wild-type and homozygous α-synuclein knock-out mice were treated with sub-chronic and prolonged, chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the sub-chronic model, wild-type and α-synuclein knock-out mice were treated for five consecutive days with MPTP (1–25 mg/kg, s.c.) or vehicle, and sacrificed 3 days following the last injection. The prolonged, chronic model consisted of two injections of MPTP (1–20 mg/kg, s.c.) per week for 5 weeks, with co-administration of probenecid (250 mg/kg, i.p.), and animals were sacrificed 3 weeks following the last injection. Sub-chronic administration of MPTP caused a dramatic, dose-dependent decrease in striatal dopamine (DA) concentrations, while an attenuated response was observed in α-synuclein knock-out mice. Similarly, prolonged, chronic administration of MPTP produced a dose-dependent decrease in striatal DA concentrations, and a corresponding loss of striatal vesicular monoamine transporter (VMAT-2) protein in wild-type mice. However, mice lacking α-synuclein had an attenuated loss of striatal DA concentrations, while no loss of striatal VMAT-2 protein was observed. Both sub-chronic and prolonged, chronic administration of MPTP caused an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC) to DA ratio in wild-type mice, but not in mice lacking α-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in α-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that α-synuclein null mice have an attenuated response to the toxic effects of MPTP exposure, even over prolonged periods of time and that the biochemical sequela of a protracted insult to nigrostriatal DA neurons are distinct between mice with and without α-synuclein expression.

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.

Morphine blood-brain barrier transport is influenced by probenecid co-administration.

The objective of this study was to investigate the possible influence of probenecid on morphine transport across the blood-brain barrier (BBB) in rats. Microdialysis probes, calibrated using retrodialysis by drug, were placed into the striatum and jugular vein of seven Sprague-Dawley rats. Morphine was administered as a 4-h exponential infusion. The experiment was repeated the next day with the addition of probenecid, administered as a bolus dose (20 mg/kg) followed by a constant infusion (20 mg/kg/h). Models for BBB transport were built using the computer program NONMEM. The steady-state ratio of 0.29 +/- 0.07 of unbound morphine concentration in brain to that in blood indicates that morphine is actively effluxed at the BBB. Probenecid co-administration increased the ratio to 0.39 +/- 0.04 (p < 0.05). Models in which probenecid influenced the brain efflux clearance rather than the influx clearance, well described the data. The half-life in brain increased from 58 +/- 9 min to 115 +/- 25 min when probenecid was co-administered. Systemic clearance of morphine also decreased upon probenecid co-administration, and M3G formation was decreased. This study indicates that morphine is a substrate for the probenecid-sensitive transporters at the BBB. Co-administration of probenecid decreased the brain efflux clearance of morphine.

The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats

In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3-glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812±0.034 for M6G alone, 0.0824±0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats.

Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats.

To ameliorate the late-onset of severe gastrointestinal toxicity provoked by irinotecan (CPT-11), which may be related to the biliary excretion of CPT-11 and/or its metabolites. Effects of probenecid, an inhibitor of MRP2/ABCC2, on the biliary excretion and mucosal intestinal tissue concentration of CPT-11 and its metabolites were examined in rats. CPT-11-induced late-onset gastrointestinal toxicity was also evaluated. Coadministration of probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38) and its glucuronide by half with a concomitant increase in their plasma concentration. When the dose of CPT-11, in the presence of probenecid, was set at half that in its absence, the plasma SN-38 concentration was maintained at the same level as the control, whereas the mucosal intestinal tissue concentration of SN-38 was reduced. Under this condition, CPT-11-induced watery diarrhea, changes in intestinal marker enzymes and body weight reduction were much less in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as that in the control. Coadministration of probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.

Sex-related differences in the renal disposition of the acidic metabolite of clentiazem in rat

1. Sex-related differences in the renal excretion of the acidic compounds (+)-(2 S, 3 S) 8-chloro-2,3,4,5-tetrahydro-3-hydroxy-2-(4-hydroxyphenyl)-4-oxo-1,5-benzothiaz 5-acetic acid (MA4; one of the acidic metabolites of clentiazem), probenecid (PB) and methotrexate (MTX) have been investigated in the 7-week-old male and female SpragueDawley rat using an in vivo renal clearance technique. 2. The extent of plasma protein binding of MA4, PB and MTX was ~96, 95 and 65%, respectively, and it did not differ significantly between the male and female rat. On the other hand, the unbound renal clearance (CLrf) of MA4 in the female was ~300 times higher than that in male, and the ratio of this clearance to the glomerular filtration rate (GFR) was ~10, suggesting that MA4 undergoes extensive active renal secretion in the female. Furthermore, the CLrf/GFR ratio was significantly decreased by co-administration of PB. In contrast, no sex-related difference in the renal excretion of PB could be detected because its CLrf was very low and reabsorption contributed extensively to its renal disposition. The CLrf/GFR for MTX was ~2.5 but did not differ significantly between the male and female. 3. The renal organic anion transport systems in rat show sex-related differences and have different substrate-specific characteristics.