No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.

Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9.

Effect of Water Extract of Mangosteen Pericarp on Donepezil Pharmacokinetics in Mice.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb-drug combinations have been increasingly attempted to alleviate Alzheimer's disease (AD), the PK evaluation of herb-drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs. Recently, the memory-enhancing effects of water extract of mangosteen pericarp (WMP) has been reported, suggesting a potential for the combination of WMP and donepezil (DNP) for AD treatment. Thus, it was evaluated how WMP affects the PK change of donepezil, including systemic exposure and tissue distribution in mice after simultaneous oral administration of DNP with WMP. Firstly, co-treatment of WMP and donepezil showed a stronger inhibitory effect (by 23.0%) on the neurotoxicity induced by Aß(25-35) in SH-SY5Y neuroblastoma cells than donepezil alone, suggesting that the combination of WMP and donepezil may be more effective in moderating neurotoxicity than donepezil alone. In PK interaction, WMP increased donepezil concentration in the brain at 4 h (by 63.6%) after administration without affecting systemic exposure of donepezil. Taken together, our results suggest that WMP might be used in combination with DNP as a therapy for AD.

Effect of treatment period with LC478, a disubstituted adamantayl derivative, on P-glycoprotein inhibition: its application to increase docetaxel absorption in rats.

1. Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. 2. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-gp were evaluated.3. The 7-day treatment with LC478 increased docetaxel absorption via intestinal P-gp inhibition in rats. Intestinal concentrations of LC478 were 8.31-10.3 µM in rats after 7-day treatment of LC478. These concentrations were close to 10 µM that reduced P-gp mediated docetaxel efflux and P-gp expression in MDCK-MDR1 cells. Considering that intestinal LC478 concentrations after 1-day treatment were 2.68-4.19 µM, higher LC478 concentrations after 7-day treatment might have driven P-gp inhibition and increased docetaxel absorption. LC478 might competitively inhibit P-gp considering its stimulated ATPase activity and its binding site with nucleotide binding domain of P-gp. 4. Therefore, repeated treatment with LC478 can determine its feasibility for P-gp inhibition and changing docetaxel bioavailability.

Pharmacokinetics, tissue distribution, and tentative metabolite identification of sauchinone in mice by microsampling and HPLC-MS/MS methods.

Sauchinone, a biologically active lignan found in Saururus chinensis (Saururaceae), exerts various biological activities against jaundice, inflammatory disease, hepatic steatosis, and oxidative injury. Despite its diverse applications, there exists some information about sauchinone's pharmacokinetics but its tissue distribution, metabolism, and tentative metabolites have not been reported yet. Thus we investigated the pharmacokinetics of sauchinone in mice using microsampling and HPLC-MS/MS methods. Sauchinone presented linear pharmacokinetics at intravenous doses 7.5-20 mg/kg and oral doses 20-500 mg/kg. However, the metabolism of sauchinone was saturated and this agent presented nonlinear pharmacokinetics at 50 mg/kg in the intravenous study. At sauchinone 20 mg/kg the F of sauchinone was 7.76% of the oral dose despite that 77.9% of sauchinone was absorbed. This might be due to extensive metabolism of sauchinone in S9 fractions of liver and small intestine. Tentative metabolites of sauchinone by oxidation, dioxidation, methylation, demethylation, dehydrogenation, or bis-glucuronide conjugation were detected in plasma and S9 fractions of liver, intestine, and kidney. The distribution of sauchinone was considerably high (tissue-to-plasma (T/P) ratios, >1) in liver, small intestine, kidney, lung, muscle, fat, or mesentery after intravenous and oral administration and in stomach and large intestine only after oral administration. The protein binding value of sauchinone was 53.0%. These pharmacokinetic data of sauchinone provide an important basis for preclinical applications and experimental methods can be adjusted to evaluate the pharmacokinetics of natural products in mice.

A new approach for pharmacokinetic studies of natural products: measurement of isoliquiritigenin levels in mice plasma, urine and feces using modified automated dosing/blood sampling system.

The present study was undertaken to investigate the pharmacokinetics of isoliquiritigenin (isoLQ) as determined by the automated dosing/blood sampling (ABS) and traditional manual blood sampling techniques in awake and freely moving mice using combined liquid chromatography tandem mass spectrometry. Pharmacokinetic comparison was conducted by allocating mice into two groups; an ABS group (intravenous study and oral studies, n = 5 each) and a manual group (intravenous and oral studies; n = 5 each). Significant differences in pharmacokinetic parameters (area under the curve and clearances) were observed between ABS and manual groups. This could be mainly due to the blood sampling site difference (via heart puncture in traditional manual group and via carotid artery in ABS groups). The low F of isoLQ could be mainly due to a considerable gastrointestinal and/or hepatic first-pass effect and not to incomplete absorption. The driving force for distribution and elimination of drugs is its concentration in the arterial blood. Therefore, the ABS method was found to be a useful drug development tool for accelerating the process of preclinical in vivo studies and for obtaining reliable and accurate pharmacokinetic parameters in mice.

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice.

Mirabegron (MBR) is a ß3-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F24h and AUC0-24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143-195% compared with the MBR rats. The absolute F24h, relative F24h, and AUC0-24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178-234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR.

Pharmacokinetic Feasibility of Stability-Enhanced Solid-State (SESS) Tenofovir Disoproxil Free Base Crystal.

Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread®) has been marketed due to the hydrolysis of TD in moisture. Recently, a stability-enhanced solid-state TD free base crystal (SESS-TD crystal) was developed with improved solubility (192% of TEV) under gastrointestinal pH condition and stability under accelerated conditions (40 °C, RH 75%) for 30 days. However, its pharmacokinetic property has not been evaluated yet. Therefore, this study aimed to evaluate the pharmacokinetic feasibility of SESS-TD crystal and to determine whether the pharmacokinetic profile of TEV remained unchanged when administering SESS-TD crystal stored for 12 months. In our results, the F and systemic exposure (i.e., AUC and Cmax) of TEV in the SESS-TD crystal and TDF groups were increased compared to those in the TEV group. The pharmacokinetic profiles of TEV between the SESS-TD and TDF groups were comparable. Moreover, the pharmacokinetic profiles of TEV remained unchanged even after the administration of the SESS-TD crystal and TDF stored for 12 months. Based on the improved F after the SESS-TD crystal administration and the stable condition of the SESS-TD crystal after 12 months, SESS-TD crystal may have enough pharmacokinetic feasibility to replace TDF.

Change of metformin concentrations in the liver as a pharmacological target site of metformin after long-term combined treatment with ginseng berry extract.

Metformin as an oral glucose-lowering drug is used to treat type 2 diabetic mellitus. Considering the relatively high incidence of cardiovascular complications and other metabolic diseases in diabetic mellitus patients, a combination of metformin plus herbal supplements is a preferrable way to improve the therapeutic outcomes of metformin. Ginseng berry, the fruit of Panax ginseng Meyer, has investigated as a candidate in metformin combination mainly due to its anti-hyperglycemic, anti-hyperlipidemic, anti-obesity, anti-hepatic steatosis and anti-inflammatory effects. Moreover, the pharmacokinetic interaction of metformin via OCTs and MATEs leads to changes in the efficacy and/or toxicity of metformin. Thus, we assessed how ginseng berry extract (GB) affects metformin pharmacokinetics in mice, specially focusing on the effect of the treatment period (i.e., 1-day and 28-day) of GB on metformin pharmacokinetics. In 1-day and 28-day co-treatment of metformin and GB, GB did not affect renal excretion as a main elimination route of metformin and GB therefore did not change the systemic exposure of metformin. Interestingly, 28-day co-treatment of GB increased metformin concentration in the livers (i.e., 37.3, 59.3% and 60.9% increases versus 1-day metformin, 1-day metformin plus GB and 28-day metformin groups, respectively). This was probably due to the increased metformin uptake via OCT1 and decreased metformin biliary excretion via MATE1 in the livers. These results suggest that co-treatment of GB for 28 days (i.e., long-term combined treatment of GB) enhanced metformin concentration in the liver as a pharmacological target tissue of metformin. However, GB showed a negligible impact on the systemic exposure of metformin in relation to its toxicity (i.e., renal and plasma concentrations of metformin).

Pharmacokinetic interaction between metoprolol and SP-8203 in rats: competitive inhibition for the metabolism of metoprolol by SP-8203 via hepatic CYP2D subfamily.

1. The occurrence of cerebral ischemia is prevalent in patients with hypertension and the combination drug therapy is needed. Thus, the pharmacokinetic interaction between metoprolol (anti-hypertension drug) and SP-8203 (a new drug candidate for cerebral ischemia) with respect to the metabolism via CYP isozymes was evaluated. 2. Metoprolol and SP-8203 were administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine in in vivo studies, the disappearance and apparent K(i) of each drug in in vitro microsomes and [I]/K(i) ratios for each drug were determined. In addition, the disappearance of each drug via CYPs in rat and human microsomes were measured. 3. The AUC and CL(NR) of intravenously administered metoprolol with SP-8203 were significantly greater and slower, respectively, than without SP-8203. However, pharmacokinetic parameters of oral metoprolol and intravenous/oral SP-8203 were not altered. 4. The hepatic metabolism of metoprolol via CYP2D was inhibited by SP-8203 in a competitive manner. However, the intestinal metabolism of metoprolol was not influenced by SP-8203. SP-8203 was not metabolized via CYP isozymes in rats and then co-administration of metoprolol did not affect the metabolism of SP-8203.

Pharmacokinetic Interaction between Metformin and Verapamil in Rats: Inhibition of the OCT2-Mediated Renal Excretion of Metformin by Verapamil.

The incidence of hypertension in diabetic patients has been increasing and contributing to the high mortality of diabetic patients. Recently, verapamil use was found to lower fasting blood glucose levels in diabetic patients, which led to a new indication of verapamil as combination treatment with anti-diabetic agents such as metformin. As pharmacokinetic (PK) interaction can affect drug efficacy and safety in drug combination, their PK-based interaction is recommended to be evaluated in preclinical levels as well as clinical levels. In case of metformin and verapamil, organic cation transporter (OCT) 1 and 2 primarily mediate metformin distribution to the liver and its elimination into urine, whereas cytochrome P450 is responsible for the hepatic metabolism of verapamil. Verapamil is also known as a potential OCT2 inhibitor. Thus, PK interaction between metformin (30 mg/kg) and verapamil (20 mg/kg) were investigated after their simultaneous administration to rats. In our results, verapamil inhibited the OCT2-mediated renal excretion of metformin, subsequently leading to increase of the systemic exposure of metformin. In contrast, metformin did not influence the pharmacokinetic pattern of verapamil. Although the further clinical investigation is required, our finding suggests a possibility of OCT2-mediated interaction of metformin and verapamil.

LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats.

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6⁻20.5, from (LC478 concentration in intestine, 9.37⁻12.3 µM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 µM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

Lonicera japonica extract increases metformin distribution in the liver without change of systemic exposed metformin in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Flower and flower bud of Lonicera japonica, Lonicerae Flos, have been popularly used as medicinal plant for the treatment of clearing heat and thirst, thereby improving diabetic or diabetic associated symptoms (thirst and poor eyesight). AIM OF THE STUDY: Organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) are known to play important roles in metformin transport in the liver and kidneys. Thus, there might be interactions between Lonicerae Flos and metformin via OCTs and MATEs. Also treatment period has been issued in transporter-mediated drug interactions. The objective of this study was to determine the effect of Lonicerae Flos ethanol extract (LJ) on metformin pharmacokinetics and its glucose lowering activity in different treatment periods. MATERIALS AND METHODS: Effect of LJ on metformin uptake was evaluated in vitro HEK-293 cells expressing human OCTs or MATEs. Treatment period-dependent impact of LJ on systemic exposure and hepatic distribution of metformin as well as its glucose tolerance activity were assessed in in vivo rats. RESULTS: LJ substantially inhibited MATE1-mediated metformin uptake in vitro. In evaluating treatment period effects of LJ and metformin, 1-, 7-, and 28-day co-treatments of LJ with metformin did not change systemic exposure of metformin compared to those in metformin alone. Whereas, 28-day co-treatment of LJ with metformin increased metformin concentration in liver as a pharmacological target site of metformin. It could be due to the reduced MATE1-mediated metformin efflux from hepatocytes to bile by MATE1 inhibition in liver. Glucose tolerance activity was also enhanced by 28-day co-treatment of LJ and metformin compared to metformin alone. CONCLUSIONS: In 28-day co-treatment of LJ and metformin, LJ increased metformin concentration in liver and improved glucose tolerance activity without systemic exposure change of metformin, suggesting the importance to consider treatment period effect and both systemic exposure and tissue distribution in drug interactions.

Dose-Independent ADME Properties and Tentative Identification of Metabolites of α-Mangostin from Garcinia mangostana in Mice by Automated Microsampling and UPLC-MS/MS Methods.

The information about a marker compound's pharmacokinetics in herbal products including the characteristics of absorption, distribution, metabolism, excretion (ADME) is closely related to the efficacy/toxicity. Also dose range and administration route are critical factors to determine the ADME profiles. Since the supply of a sufficient amount of a marker compound in in vivo study is still difficult, pharmacokinetic investigations which overcome the limit of blood collection in mice are desirable. Thus, we have attempted to investigate concurrently the ADME and proposed metabolite identification of α-mangostin, a major constituent of mangosteen, Garcinia mangostana L, in mice with a wide dose range using an in vitro as well as in vivo automated micro-sampling system together. α-mangostin showed dose-proportional pharmacokinetics at intravenous doses of 5-20 mg/kg and oral doses of 10-100 mg/kg. The gastrointestinal absorption of α-mangostin was poor and the distribution of α-mangostin was relatively high in the liver, intestine, kidney, fat, and lung. α-mangostin was extensively metabolized in the liver and intestine. With regards to the formation of metabolites, the glucuronidated, bis-glucuronidated, dehydrogenated, hydrogenated, oxidized, and methylated α-mangostins were tentatively identified. We suggest that these dose-independent pharmacokinetic characteristics of α-mangostin in mice provide an important basis for preclinical applications of α-mangostin as well as mangosteen. In addition, these experimental methods can be applied to evaluate the pharmacokinetics of natural products in mice.

Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models.

The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC50 of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels.

Effects of cysteine on the pharmacokinetics of paclitaxel in rats.

Paclitaxel is a P-gp substrate and metabolized via CYP2C and 3A subfamily in rats. It has been reported that cysteine causes the changes in expression of CYP isozymes and intestinal P-gp mediated efflux activity in rats. Thus, the effects of cysteine on the pharmacokinetics of intravenous and oral paclitaxel were investigated in rats. After intravenous administration of paclitaxel (30 mg/kg) to control (CON), single cysteine treatment (ST) and cysteine treatment for a week (CT) rats, the pharmacokinetic parameters were comparable among three groups of rats. Also the pharmacokinetic parameters between CON and ST rats were comparable after oral administration of paclitaxel (30 mg/kg) to rats. These results are consistent with that oral cysteine supplement on a single day did not considerably inhibit the metabolism of paclitaxel via hepatic and/or intestinal CYP3A subfamily and P-gp mediated efflux of paclitaxel in the liver and/or intestine both after intravenous and oral administration to rats. After oral administration of paclitaxel (30 mg/kg) to rats, the greater AUC(06 h) in CT rats was mainly due to that oral cysteine supplement for seven consecutive days enhanced the gastrointestinal absorption of paclitaxel compared with those in CON and ST rats.

Reduced clearance of ε-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate.

OBJECTIVES: Anti-ulcer drugs are frequently used in patients with acute renal failure (ARF). Zinc acexamate is ionized to zinc and ε-acetamidocaproic acid and free EACA exerts a potent therapeutic effect in treating gastric or duodenal ulcers with few side effects. Thus, pharmacokinetic changes in rats with acute renal failure induced by uranyl nitrate (U-ARF rats) were investigated in this study. METHODS: The in-vivo pharmacokinetics and in-vitro hepatic/intestinal metabolism of EACA were assessed using control and U-ARF rats. The mechanism of urinary excretion of EACA was further investigated in rats. KEY FINDINGS: After intravenous and oral administration of zinc acexamate to U-ARF rats, there were significant increases in the values of the area under the curve (AUC) and decreases in the values for time-averaged renal and nonrenal clearances (Cl(r) and Cl(nr) , respectively) compared with control rats. Slower Cl(nr) was partly due to a decrease in the metabolism in liver and/or intestine. Slower Cl(r) could have been due to urine flow rate-dependent timed-interval renal clearance, decrease in organic anion transporter-mediated renal excretion (drug interaction with probenecid and decrease in the relative contribution of net secretion compared with glomerular filtration in U-ARF rats) and/or impaired kidney function. CONCLUSIONS: The pharmacokinetics were significantly altered in U-ARF rats due to the changes in both the hepatic/intestinal metabolism and urinary excretion.