Hepatic fibrosis does not affect the pharmacokinetics of 5-fluorouracil in rats

In the case of cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil (5‐FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5‐FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5‐FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate‐limiting enzyme in 5‐FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5‐FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5‐FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

Dose‐dependent pharmacokinetics and first‐pass effects of mirodenafil,a new erectogenic,in rats

The pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous (5, 10, 20 and 50 mg/kg) and oral (10, 20 and 50 mg/kg) administration of mirodenafil, and the first‐pass effect of mirodenafil after intravenous, oral, intraportal, intragastric and intraduodenal (20 mg/kg) administration of mirodenafil were evaluated in rats. The pharmacokinetics of mirodenafil and SK3541 were dose‐dependent after both intravenous and oral administration of mirodenafil due to the saturable hepatic metabolism of mirodenafil. After oral administration of mirodenafil, approximately 2.59% of the oral dose was not absorbed, the F value was approximately 29.4%, and the hepatic and gastrointestinal first‐pass effects of mirodenafil were approximately 21.4% and 54.3% of the oral dose, respectively. The low F value of mirodenafil in rats was mainly due to considerable hepatic and gastrointestinal first‐pass effects in rats. The equilibrium plasma‐to‐blood cell partition ratios of mirodenafil were independent of the initial blood mirodenafil concentrations of 1–10 µg/ml; the mean values were 1.08–1.21. The plasma binding values of mirodenafil to rat plasma was 87.8%. Copyright © 2009 John Wiley & Sons, Ltd.     

Investigating the bioavailabilities of olerciamide A via the rat's hepatic,gastric and intestinal first‐pass effect models

Olerciamide A (OA) is a new alkaloid isolated from Portulaca oleracea L. that has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons for its low bioavailability, hepatic, gastric and intestinal first‐pass effect models were established, and a rapid, sensitive UHPLC method was validated and applied for the determination after dosing via the femoral, portal, gastric and intestinal routes. As inhibitors of CYP3A and P‐gp, verapamil, midazolam and borneol in low and high dose groups were selected to improve the low bioavailability of olerciamide A. Moreover, a rectal administration method was also carried out to improve the bioavailability of olerciamide A. The results showed that the bioavailability of olerciamide A using hepatic, gastric and intestinal routes were 92.16%, 84.88% and 5.76%, respectively. The areas under the plasma concentration–time curve from zero to infinity (AUC_{0 → ∞}) were increased a little after being dosed with 10 and 30 mg/kg verapamil (p > 0.05), but markedly increased after being dosed with 0.4 and 1.2 mg/kg midazolam as well as 8 and 24 mg/kg borneol (p < 0.05). Besides, the AUC_0 → ∞ values after the lower and upper rectal administrations were separately similar to the intravenous and intraportal administrations. Our study showed that the intestinal first‐pass effect mainly contributed to the low bioavailability of olerciamide A in rats due to it being a substrate of CYP3A and P‐gp as well as to its poor intestinal absorption.     

Effect of dimethylnitrosamine‐induced liver dysfunction on the pharmacokinetics of 5‐fluorouracil after administration of S‐1, an antitumour drug,to rats

Objectives The anti‐tumour agent S‐1 comprises tegafur (a prodrug of 5‐fluorouracil; 5‐FU), gimeracil (2‐chloro‐2,4‐dihydroxypyridine (CDHP); a competitive inhibitor of 5‐FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5‐FU after administration of S‐1 to rats was investigated. Methods S‐1 (5 mg/kg) was administered intravenously and orally to rats with DMN‐induced liver dysfunction. Plasma concentrations of S‐1 components and 5‐FU were measured by HPLC and LC/MS‐MS. Blood tests and in‐vitro enzymatic investigations were also conducted. Key findings DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5‐FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S‐1, the blood concentration‐time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half‐life of tegafur was significantly prolonged. The maximum plasma concentration (C_max) of 5‐FU was significantly reduced and the area under the blood concentration‐time curve (AUC) was reduced by 22%. Following oral administration, the C_max of tegafur, 5‐FU and CDHP were significantly decreased and half‐lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5‐FU (13.6% reduction). Conclusions The pharmacokinetic profiles of tegafur, 5‐FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5‐FU. However, hepatic dysfunction had less of an effect on the AUC of 5‐FU, which correlates with anti‐tumour effect, after the oral administration of S‐1.     

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

GL‐V9, a derivative of wogonin, has potent anti‐cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL‐V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL‐V9, an in situ single‐pass perfusion model and a Caco‐2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (F_a × F_g) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (F_{gut wall}) was 98.59 ± 9.74%, while the hepatic bioavailability (F_h) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL‐V9. The effective permeability (P_eff) in the duodenum and jejunum was 1.34 ± 0.50 × 10^?4 and 0.90 ± 0.27 × 10^?4 cm/s, respectively. The high permeability of GL‐V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Cl_{int, CYP450s and UGT} of GL‐V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL‐V9 possesses higher permeability than wogonin and the metabolism of GL‐V9 is related to its disposition in rat intestine and liver.     

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.     

Synthesis and purification of [2‐13C]‐5‐fluorouracil

[2‐¹³C]‐5‐Fluoropyrimidine‐2,4(1H,3H)‐dione ([2‐¹³C]‐5‐fluorouracil or [2‐¹³C]‐5‐FU) is a potential diagnostic agent for measuring 5‐FU‐induced toxicity in cancer patients. It was prepared and purified with isotopic and chemical purity of>99% on a multigram scale in a two‐step synthesis from [¹³C]‐urea. Preparative separation of [2‐¹³C]‐FU and [2‐¹³C]‐uracil was carried out by automated medium pressure silica gel column chromatography. The method is applicable to a broader range of 5‐FU isotopic analogs derived from labeled uracil. Copyright © 2011 John Wiley & Sons, Ltd.     

Influence of vasomodulators and tumor transplantation on the disposition of 5‐fluorouracil after application to the liver surface in rats

This study investigated the effect of epinephrine (a vasoconstrictor) and hydralazine (a vasodilator) on the hepatic disposition of 5‐fluorouracil (5‐FU) after application to the surface of the liver in rats. Normal livers were compared with a Walker 256 carcinoma cell tumor model. A cylindrical diffusion cell was attached to the liver surface. 5‐Fluorouracil was added into the diffusion cell in combination with vasomodulators or after pretreatment with epinephrine. After selected treatment times, the 5‐FU concentrations were assayed at three sites in the excised livers. The 5‐FU concentration in the region under the cell attachment site (site 1) was significantly higher after concomitant application of 5‐FU and epinephrine, compared with 5‐FU alone, and increased in an epinephrine dose‐dependent manner. On the other hand, preferential distribution of 5‐FU at site 1 was not seen when applied in combination with hydralazine. After 10 min of epinephrine pretreatment, the concentration of 5‐FU at site 1 was approximately two times higher than that for the control. Furthermore, the 5‐FU concentration at site 1 of the tumor model was greatly increased compared with the normal liver. These results suggest that application of epinephrine to the liver surface might enhance the accumulation of 5‐FU at the desired target site.     

Development and validation of an infrared spectroscopy‐based method for the analysis of moisture content in 5‐fluorouracil

The determination of moisture content in pharmaceuticals is very important as moisture is mainly responsible for the degradation of drugs. Degraded drugs have reduced efficacy and could be hazardous. The objective of the present work is to replace the Karl Fischer (KF) titration method used for moisture analysis with a method that is rapid, involves no toxic materials and is more effective. Diffuse reflectance infrared (IR) spectroscopy, which is explored as a potential alternative to various approaches, is investigated for moisture analysis in 5‐fluorouracil, an anticancer drug. A total of 150 samples with varying moisture content were prepared in laboratory by exposing the drug at different relative humidities, for different time intervals. Infrared spectra of these samples were collected with a Fourier transform infrared (FTIR) spectrophotometer using a diffuse reflectance accessory. Reference moisture values were obtained using the Karl Fischer titration method. A number of calibration models were developed using the partial least squares (PLS) regression method. A good correlation was obtained between predicted IR values and reference values in the calibration and validation set. The derived calibration curve was used to predict moisture content in unknown samples. The results show that IR spectroscopy can be used successfully for the determination of moisture content in the pharmaceutical industry. Copyright © 2009 John Wiley & Sons, Ltd.     

Thermal stability studies of 5‐fluorouracil using diffuse reflectance infrared spectroscopy

5‐Fluorouracil is one of the oldest chemotherapy drugs and it has been in use for decades. It is an active medicine against several types of cancer and effectively blocks the replication of DNA viruses. The present study assessed the potential of diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy to determine the thermal stability of 5‐fluorouracil. Infrared spectra of the drug before and after exposure to thermal radiation at different temperatures were collected in diffuse reflectance mode using a Fourier transform infrared (FTIR) spectrophotometer. Differential scanning calorimetry (DSC) and X‐ray diffraction (XRD) analysis were carried out simultaneously to confirm and support the results of infrared spectroscopy. The DRIFT spectra reveal that the drug shows good thermal stability up to 275 °C and undergoes complete thermal breakdown at about 285 °C. The results of DSC and XRD analysis also give the same information, which support the implementation of diffuse reflectance infrared spectroscopy for the determination of thermal stability of 5‐fluorouracil. Copyright © 2009 John Wiley & Sons, Ltd.     

Physiologically based pharmacokinetic modeling revealed minimal codeine intestinal metabolism in first‐pass removal in rats

The physiologically based model with segregated flow to the intestine (SFM‐PBPK; partial, lower flow to enterocyte region vs. greater flow to serosal region) was found to describe the first‐pass glucuronidation of morphine (M) to morphine‐3β‐glucuronide (MG) in rats after intraduodenal (i.d.) and intravenous (i.v.) administration better than the traditional model (TM), for which a single intestinal flow perfused the whole of the intestinal tissue. The segregated flow model (SFM) described a disproportionately greater extent of intestinal morphine glucuronidation for i.d. vs. i.v. administration. The present study applied the same PBPK modeling approaches to examine the contributions of the intestine and liver on the first‐pass metabolism of the precursor, codeine (C, 3‐methylmorphine) in the rat. Unexpectedly, the profiles of codeine, morphine and morphine‐3β‐glucuronide in whole blood, bile and urine, assayed by LCMS, were equally well described by both the TM‐PBPK and SFM‐PBPK. The fitted parameters for the models were similar, and the net formation intrinsic clearance of morphine (from codeine) for the liver was much higher, being 9‐ to 13‐fold that of the intestine. Simulations, based on the absence of intestinal formation of morphine, correlated well with observations. The lack of discrimination of SFM and TM with the codeine data did not invalidate the SFM‐PBPK model but rather suggests that the liver is the only major organ for codeine metabolism. Because of little or no contribution by the intestine to the metabolism of codeine, both the TM‐ and SFM‐PBPK models are equally consistent with the data. Copyright © 2016 John Wiley & Sons, Ltd.     

Radiolabeling and in vitro evaluation of a new 5‐fluorouracil derivative with cell culture studies

The clinical impact and accessibility of ^99mTc tracers for cancer diagnosis would be greatly enhanced by the availability of a new, simple, and easy labeling process and radiopharmaceuticals. 5‐Fluorouracil is an antitumor drug, which has played an important role for the treatment of breast carcinoma. In the present study, a new derivative of 5‐Fluorouracil was synthesized as (1‐[{1′‐(1′′‐deoxy‐2′′,3′′:4′′,5′′‐di‐O‐isopropylidene‐β‐D‐fructopyranose‐1′′‐yl)‐1′H‐1′,2′, 3′‐triazol‐4′‐yl}methyl]‐5‐fluorouracil) ( E ) and radiolabeled with ^99mTc. It was analyzed by radio thin layer chromatography for quality control and stability. The radiolabeled complex was subjected to in vitro cell‐binding studies to determine healthy and cancer cell affinity using HaCaT and MCF‐7 cells, respectively. In addition, in vitro cytotoxicity studies of compound E were performed with HaCaT and MCF‐5 cells. The radiochemical purity of the [^99mTc]Tc E was found to be higher than 90% at room temperature up to 6 hours. The radiolabeled complex showed higher specific binding to MCF‐7 cells than HaCaT cells. IC₅₀ values of E were found 31.5 ± 3.4 μM and 20.7 ± 2.77 μM for MCF‐7 and HaCaT cells, respectively. The results demonstrated the potential of a new radiolabeled E with ^99mTc has selective for breast cancer cells.     

Effect of Huang‐Lian‐Jie‐Du‐Decoction on pharmacokinetics of verapamil in rats

Objectives The aim was to investigate the effect of Huang‐Lian‐Jie‐Du‐Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Methods Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD‐treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. Key findings HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC_0–480 of verapamil and a 25% reduction in the AUC_0–480 of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. Conclusions HLJDD displayed a route‐dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first‐pass verapamil metabolism in the intestine.     

Contribution of a significant first‐pass effect of dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylene dioxybiphenyl‐2,2′‐dicarboxylate in the liver to its poor bioavailability in rats

Objectives The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4′,4′-dimethoxy-5,6,5′,6′-dimethylene dioxy-biphenyl-2,2′-dicarboxylate (DDB), a hepatoprotective agent, in rats. Methods DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium. Key findings A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (F_H) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 ± 0.229 × 10⁻⁵ cm/s) and in Caco-2 cell monolayers (6.8 ± 0.70 × 10⁻⁵ cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium. Conclusions These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.     

高效毛细管电泳法测定氟尿嘧啶注射液中5-氟尿嘧啶的含量

目的建立高效毛细管电泳(HPEC)测定氟尿嘧啶注射液中氟尿嘧啶(5-FU)含量的方法.方法运用高效毛细管电泳方法,熔融石英毛细管(50 cm×57 cm,75 μm),缓冲液10 mmol·L-1磷酸二氢钠(pH 5.5),检测波长280 nm,分离电压15kV,用微孔滤膜过滤后进样,压力进样6 s.结果方法最低检测浓度为0.1 mg·L-1,线性范围5～200mg·L-1,r=0.999 0,线性关系良好.日内RSD为2.3%,日间RSD为2.7%,回收率为99.7%.结论本法简单、灵敏经济,可作为氟尿嘧啶注射液中氟尿嘧啶的含量的测定方法.     

Pharmacokinetics of bicyclol in rats with acute hepatic failure

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl₄)-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl₄ intoxication in rats. The area under the curve (AUC)_(0–∞), C_max, and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l^?1, 18.8 mg l^?1, and 1.8 l h^?1 kg^?1 in control rats, and 130 mg h l^?1, 33.1 mg l^?1, and 0.15 l h^?1 kg^?1 in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl₄-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.     

Effect of itraconazole on the pharmacokinetics of everolimus administered by different routes in rats

The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2 mg/kg) or intraintestinally (0.5 mg/kg). Blood concentrations of everolimus were measured up to 240 min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20 mg/kg) significantly increased the area under the concentration–time curve (AUC) of intraintestinally administered everolimus about 4.5‐fold, but even at 50 mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50 mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2‐fold. Using a value for hepatic blood flow from the literature (50 ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20 mg/kg) changed the apparent intestinal extraction by 0.26‐fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50 mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first‐pass extraction of this drug. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.