Enhancement of oral bioavailability of paclitaxel after oral administration of Schisandrol B in rats

Paclitaxel is a substrate of the efflux transporters such as P‐glycoprotein, and is mainly metabolized by the liver. Schisandrol B (Sch B), one of the active components in Schisandra, has been reported to be able to inhibit the activity of P‐gp and CYP3A. It might be possible that Sch B would alter the pharmacokinetic behavior of paclitaxel. Therefore, the purpose of this study was to investigate the effect of Sch B on the pharmacokinetics of paclitaxel administered orally and intravenously in rats. Paclitaxel were administered to rats orally (30 mg/kg) or intravenously (0.5 mg/kg) with or without the concomitant administration of Sch B (10 or 25 mg/kg). Oral pharmacokinetic parameters of paclitaxel were significantly altered when pretreated with Sch B. There were significant increases in AUC_0‐24h (from 297.7±110.3 to 838.9±302.1 h*ng/ml; p<0.05) and C_max (from 51.7±20.1 to 136.4±35.5 ng/ml; p<0.05) in the presence of Sch B (25 mg/kg). The pharmacokinetic parameters for i.v. paclitaxel were not significantly affected by Sch B in contrast to that of oral administration. Since the presence of Sch B enhanced the systemic exposure of paclitaxel, their pharmacokinetic interaction should be taken into consideration. As the oral bioavailability of paclitaxel was increased about 3‐fold in the presence of Sch B, the concomitant use of Sch B may provide a benefit in the oral delivery of paclitaxel. Copyright © 2010 John Wiley & Sons, Ltd.     

紫杉醇超饱和自微乳化给药系统的制备及大鼠体内药动学研究

目的:制备紫杉醇超饱和自微乳化给药系统(supersaturatable self-microemulsifying drug delivery system,S-SMEDDS),并对其在大鼠体内的药动学进行研究。方法:采用伪三元相图的方法,优化紫杉醇自微乳化给药系统(SMEDDS)的处方。18只大鼠随机分为3组,分别灌胃给予10 mg/kg紫杉醇溶液、SMEDDS和S-SMEDDS,测定紫杉醇的血药浓度c、max、AUC和tmax,计算相对生物利用度。结果:确定紫杉醇SMEDDS最优处方为:油相∶表面活性剂∶助表面活性剂=50∶33∶17。油相为Lauroglycol FCC∶橄榄油(2∶1),表面活性剂为Cremophor EL∶吐温-80(1∶1),助表面活性剂为PEG-400。S-SMEDDS在此处方基础上添加5%羟丙基甲基纤维素。稀释对制剂的粒径无显著影响。SMEDDS和S-SMEDDS的粒径分别为(92.7±47.7)和(93.6±36.8)nm,粒径分布呈高斯分布。SMEDDS和S-SMEDDS的cmax和AUC显著高于溶液剂,tmax<溶液剂,生物利用度分别为333.9%和719.3%。结论:紫杉醇S-SMEDDS的口服吸收强于溶液剂和SMEDDS。     

紫杉醇纳米脂质体的制备与大鼠体内药动学

目的:制备紫杉醇新型纳米脂质体并研究其在大鼠体内的药动学。方法:采用薄膜分散超声结合冷冻干燥制备紫杉醇纳米脂质体。大鼠尾静脉注射紫杉醇脂质体及市售紫杉醇注射液Anzatax,血浆样品经乙醚提取后用反相高效液相色谱法(RP-HPLC)检测血浆紫杉醇浓度,并用3P87软件包估算药动学参数。色谱条件如下:色谱柱为Gemini ODS(150 mm×4.6 mm,5μm),流动相为0．035mol·L-1乙酸铵缓冲液(pH 5．0)-乙腈(45:50),流速1．0 mL·min,检测波长230 nm,地西泮为内标。结果:制备的紫杉醇纳米脂质体的体积权重粒径为(54.1±26．0)nm,包封率大于80％,符合药典规定,且24 h内与葡萄糖注射液配伍稳定。紫杉醇脂质体及市售紫杉醇注射液Anzatax经大鼠尾静脉注射后均符合二室模型,脂质体组的消除半衰期(t1/2β)显著长于Anzatax组[(3．38±0．39)vs．(2．49±0．63)h,P<0．05];其他药动学参数经方差分析均无显著性差异。紫杉醇脂质体与Anzatax的AUC0-8h比值为88．13％。结论:制备的紫杉醇纳米脂质体在大鼠体内的药动物参数与市售紫杉醇注射液Anzatax比较,t1/2β稍有延长,AUC0-8h值相近。     

紫杉醇纳米乳剂的体内外考察

目的考察紫杉醇纳米乳剂的形态、粒径分布及急性过敏反应,研究紫杉醇注射剂及自制紫杉醇纳米乳剂在大鼠体内的药代动力学。 方法用HPLC法测定大鼠体内紫杉醇含量。数据用3P87处理,得到各主要药代动力学参数。 结果纳米乳剂平均粒径为17.2 nm。纳米乳剂急性过敏反应为阴性,而市售紫杉醇注射液急性过敏反应为阳性。血浆中杂质及制剂中辅料不干扰紫杉醇的测定。大鼠iv自制紫杉醇纳米乳剂及紫杉醇注射液后的药-时曲线均符合二室模型。数据用3P87处理,得到各主要药代动力学参数。纳米乳剂及注射液的k₁₀分别为0.57,1.29·h^-1,k₁₂分别为1.44,1.27·h^-1,k₂₁分别为3.08,0.51·h^-1,AUC分别为34.98,21.85 mg·h·L^-1。结论紫杉醇纳米乳剂较紫杉醇注射液毒性降低,可在一定程度上延长药物在大鼠体内的循环时间。     

注射用紫杉醇脂肪乳和普通紫杉醇注射液在比格犬体内的药动学比较

目的:建立测定比格犬血浆中紫杉醇浓度的方法,并将其应用于比格犬体内注射用紫杉醇脂肪乳和普通紫杉醇注射液的药动学比较研究。方法:将注射用紫杉醇脂肪乳和普通紫杉醇注射液静脉给药1.5mg/kg后,测定比格犬血浆中的药物浓度,估算并比较药动学数据。血浆样品及内标多西他赛置于96孔板中,进行高通量的液液萃取。结果:紫杉醇的线性范围为2～500ng/ml,最低定量下限为2ng/ml,批内、批间精密度(RSD%)均<15%。分别静脉注射两种制剂后,在比格犬血浆中,紫杉醇的t1/2分别为(4.72±0.53)和(4.50±0.81)h,MRT为(2.46±0.38)和(1.82±0.59)h,AUC0～12h为(388.90±63.39)和(711.74±33.70)ng.h.ml-1,AUC0～∞为(411.89±68.44)和(738.35±45.54)ng.h.ml-1,CL为(3.71±0.46)和(2.04±0.11)L.h-1.kg-1,Vd为(9.07±1.35)和(3.65±0.91)L/kg。结论:该方法灵敏、准确、专一、简便并且实现高通量分析,适用于注射用紫杉醇脂肪乳和普通紫杉醇注射液在比格犬体内的药动学比较研究。两种制剂的主要药动学参数中c0、AUC、CL、Vd存在显著性差异(P<0.05),用梯形面积法(AUC)估算紫杉醇脂肪乳对于紫杉醇普通制剂的相对生物利用度为(54.93±10.82)%。     

紫杉醇纳米混悬剂在大鼠体内的药动学和小鼠的组织分布

目的:考察紫杉醇纳米混悬剂在大鼠体内的药动学及小鼠体内的组织分布情况。方法:将紫杉醇注射液和紫杉醇纳米混悬剂2种制剂静脉给药后,采用HPLC法分别测定给药后5,10,15,30min及1,2,4,6,8,12h时大鼠的血药浓度,给药后5,15,30min及1,2,4,8,12h时紫杉醇在小鼠心、肝、脾、肺、肾、脑组织中的含量,对2种制剂的体内生物分布特征和靶向性进行评价。结果:大鼠血浆中,紫杉醇纳米混悬剂和紫杉醇注射液的消除相半衰期分别为(5.6±0.7)和(3.8±0.4)h;AUC分别为(5.2±0.4)和(20.3±1.1)mg.h.L-1;MRT分别为(3.2±0.4)和(2.8±0.3)h;Cl分别为(2.05±0.22)和(0.56±0.19)L.kg-1.h-1。与紫杉醇注射液相比,紫杉醇纳米混悬剂在肝、脾、脑组织中的药物含量显著增加。结论:相对于市售紫杉醇注射液,紫杉醇纳米混悬剂向靶部位富集,显著降低了非靶器官的药物浓度,可减轻制剂不良反应,使药物在血浆中的循环时间延长。     

Effect of a thiolated polymer on oral paclitaxel absorption and tumor growth in rats

The anticancer agent paclitaxel is currently commercially available only as an infusion due to its low oral bioavailability. An oral formulation would be highly beneficial for patients. Besides the low solubility, the main reason for the limited oral bioavailability of paclitaxel is that it is a substrate of the efflux pump P-glycoprotein (P-gp). Recently, it has been demonstrated that P-gp can be inhibited by thiolated polymers. In this study, an oral paclitaxel formulation based on thiolated polycarbophil was evaluated in vivo in wild-type rats and in mammary cancer-induced rats. The paclitaxel plasma level after a single administration of paclitaxel was observed for 12 h in healthy rats. Moreover, cancer-induced rats were treated weekly for 5 weeks with the novel formulation. It was demonstrated that (1) co-administration of thiolated polycarbophil significantly improved paclitaxel plasma levels, (2) a more constant pharmacokinetic profile could be achieved and (3) the tumor growth was reduced. These effects can most likely be attributed to P-gp inhibition. According to the achieved results, thiolated polymers are believed to be interesting tools for the delivery of P-gp substrates such as paclitaxel.     

紫杉醇自乳化微乳的制备及其在大鼠体内的药动学

目的:制备紫杉醇微乳,并对其急性过敏反应和大鼠体内的药动学进行考察。方法:三角相图法探讨了紫杉醇自乳化微乳(以下简称自微乳)的形成条件,采用均匀设计优化组成制备自微乳。以紫杉醇注射液对照,比较自微乳豚鼠的急性过敏反应和大鼠体内的药动学。结果: 以三辛酸甘油酯三丁酸甘油酯(1 ∶1)为油相,无水乙醇作助乳化剂制备的紫杉醇自微乳经生理盐水稀释后形成稳定的微乳,平均粒径为(16±s3)nm。以紫杉醇注射液作对照,自微乳豚鼠的急性过敏反应明显降低。统计矩分析,紫杉醇自微乳与紫杉醇注射液大鼠体内平均滞留时间分别为3. 89h和2. 52h,自微乳延长药物在大鼠体内的滞留时间。结论:通过优化处方制备的紫杉醇自微乳具有较好的稳定性,并可显著降低急性过敏反应。     

Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats

Abstract

The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration–time curve (AUC_0→∞) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel.     

Clinical pharmacokinetics and oral bioavailability of ketobemidone

Summary The basic pharmacokinetics and oral bioavailability of ketobemidone have been studied in 6 patients after surgery. Plasma concentrations were first determined following intravenous administration of Ketogin^® 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and then, on the second postoperative day, following oral administration of 2 tablets of Ketogin^®, each containing ketobemidone chloride 5 mg and the spasmolytic agent 25 mg. The average oral bioavailability of ketobemidone was 34%±16% (SD, n=6). The mean plasma half-life of elimination (t_1/2) was about the same following oral (2.45±0.73 h; SD, n=5) as after intravenous administration (2.25±0.35 h; SD, n=6). The low oral bioavailability and rapid elimination of ketobemidone demonstrated in this study suggest that the usual dosage recommendation for oral Ketogin^® (ketobemidone 5–10 mg every 6–7 h) in patients with severe pain is too low.     

Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man

AIMS: To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration. METHODS: Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 microg), oral (4000 microg, aqueous suspension), intranasal (1344 microg, aqueous nasal spray) and inhaled (1000 microg ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was assessed by repeating the inhaled, intranasal and oral dosing arms together with activated charcoal, to block oral absorption. Blood samples were collected for 24 h postdose for the measurement of BDP, beclomethasone-17-monopropionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chromatography tandem mass spectrometry. RESULTS: Intravenous administration of BDP (mean CL 150 l h-1, Vss 20 l, t(1/2) 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h-1, Vss 424 l) complete conversion of BDP to B-17-MP was assumed. The resultant plasma concentrations of BOH were low and transient. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP was 2% (1-4%) and not reduced by coadministration of charcoal. The mean percentage F of the active metabolite B-17-MP was 41% (31-54%), 44% (34-58%) and 62% (47-82%) for oral, intranasal and inhaled dosing without charcoal, respectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were < 1% and 36% (27-47%), respectively. CONCLUSIONS: Unchanged BDP has negligible oral and intranasal bioavailability with limited absorption following inhaled dosing due to extensive (95%) presystemic conversion of BDP to B-17-MP in the lung. The oral and intranasal bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insignificant. The total inhaled bioavailability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this was due to pulmonary absorption. Estimates of oral bioavailability and pulmonary deposition based on total BOH were approximately half those found for B-17-MP.     

紫杉醇注射液在小鼠体内的药代动力学及组织分布

目的:建立血清中紫杉醇的分析测定方法,进行紫杉醇注射液在小鼠体内的药代动力学研究。方法:采用固相萃取方法进行血清样品预处理。色谱柱为Intertex C18(150 mm×4.6 mm,5μm),流动相为磷酸水溶液(pH3.0)-乙腈(50∶50),流速为1 mL.min-1,检测波长为227 nm。结果:紫杉醇在血清和组织中的浓度范围分别为0.39~100.00μg.mL-1和0.39~25.00μg.mL-1,准确度均在85%~115%,稳定性RSD均小于15%,小鼠静脉注射紫杉醇注射液后在小鼠体内代谢符合三房室模型(W=1/C2)。结论:本方法简便快捷,灵敏准确,本文建立的紫杉醇血药浓度测定方法和紫杉醇注射液在小鼠体内的药代动力学参数,为紫杉醇其他制剂的研究提供参考。     

Metabolism,oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats

The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro‐intestinal first‐pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K_m and V_max), the propensity for UDPGA‐dependent conjugation compared with NADPH‐dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague‐Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro‐intestinal first‐pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non‐compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration–time profiles for 10 and 25 mg/kg were consistent with high clearance (～3 L/hr/kg) and large volumes of distribution (8–12 L/hr/kg). The disposition was characterized by a terminal half‐life value of 3–4 h. After oral administration the plasma concentration–time profiles demonstrated fairly rapid absorption (t_max～1–2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ～2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first‐pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd.     

N-acetyl-L-cysteine functionalized nanostructured lipid carrier for improving oral bioavailability of curcumin: preparation,in vitro and in vivo evaluations

The application of orally administered nanoparticles in the circulation system is limited by the secretion and shedding of intestinal tract mucous layer. In order to enhance mucoadhesion and mucus penetration of curcumin (Cur)-loaded nanostructured lipid carrier (NLC) after oral administration, a new multifunctional conjugate, N-acetyl-L-cysteine-polyethylene glycol (100)-monostearate (NAPG), was synthesized. Functionalized nanocarriers (Cur-NAPG-NLC) modified by different amounts of NAPG (the amounts of NAPG were 20, 50, and 100?mg) were prepared and investigated for in vitro and in vivo behavior. Mean particle sizes of 89–141?nm with negative zeta potential (?15 to ?11?mV) and high encapsulation efficiency (EE,?>90%) possessing spherical and stable nanocarriers were observed. Sustained drug release was also observed for the NAPG-NLC. In situ intestinal perfusion studies showed that with increasing the amount of NAPG increase absorption of Cur. In vivo oral pharmacokinetic evaluation suggested that the bioavailability of Cur in rats was proportional to the degree of functionalization of NLCs with NAPG. AUC_0–t of Cur-NAPG100-NLC was improved by 499.45 and 116.89 folds as compared to that of Cur solution and unmodified Cur-NLC, respectively. In conclusion, NAPG modified NLC could be a promising drug delivery system for improving oral performance of BCS class IV drugs.     

Inhalable,large porous PLGA microparticles loaded with paclitaxel: preparation,in vitro and in vivo characterization

Abstract

Large porous particles (LPPs) could be used as a useful carrier for non-invasive delivery to the deep lung. Pulmonary delivery of paclitaxel-loaded LPPs (PTX-LPPs) can help to eliminate the highly complicated and harmful solvent used in PTX parenteral formulations. PTX-LPPs with mass median aerodynamic diameter (MMAD) of 5.74?±?0.09?μm, high encapsulation efficiency and good aerosolisation properties were produced using ammonium bicarbonate as porogen. Cytotoxicity of PTX-LPPs on A549 and Calu-6 cell lines was comparable with Free-PTX. Endotracheal administration of PTX-LPPs in rats exhibited PTX plasma concentration in the therapeutic range which lasted 4-fold longer than i.v. injection. The bioavailability was measured as 51?±?7.1%. The lung targeting efficiency (T_e) of PTX-LPPs was 11.9-fold higher than i.v. administration. PTX-LPPs could deliver a higher PTX to lung with a non-toxic plasma level in a longer duration which shows their pulmonary delivery suitability.     

The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide

AIMS: Morphine-6-glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio-respiratory effects of three alternative routes of administration of M6G. METHODS: Ten healthy volunteers participated in an open randomized study. Subjects received M6G 2 mg as an intravenous bolus, 20 mg orally, 2 mg subcutaneously and 4 mg by the nebulized route. Pulse, blood pressure, respiratory rate and peak flow rate were monitored and subjective toxicity recorded on rating and visual analogue scales. RESULTS: After i.v. M6G the mean (+/- s.d.) AUC(0,infinity) standardized to a dose of 1 mg was 223 +/- 57 nmol l(-1) h, mean elimination half-life was 1.7 +/- 0.7 h and the mean clearance was 157 +/- 46 ml min(-1). These parameters were virtually identical after subcutaneous administration which had a bioavailability (F(0,infinity)) of 102 +/- 35% (90% CI 82, 117%) and t(max) of 0.5 +/- 0.2 h. The mean bioavailability of nebulized M6G was 6 +/- 2% (90% CI 4, 7%) with a t(max) of 1.2 +/- 0.8 h. Following oral M6G two plasma M6G peaks were seen in 7 of the 10 subjects, the first with a t(max) of 3.1 (+/- 0.9) h. The second peak had a t(max) of 13.4 (+/-5.0) h, started approximately 4 h after dosing, and was associated with the detection of plasma M3G and morphine, suggesting that M6G was significantly hydrolysed in the gut to morphine, which was then glucuronidated following absorption. Although the overall mean bioavailability was 11 +/- 3% (90% CI 9, 12%), confining the analysis to data from the first peak suggested a bioavailability of directly absorbed M6G of only 4 +/- 4%. Apart from a characteristic dysphoria following intravenous and subcutaneous M6G, there was no significant toxicity. CONCLUSIONS: With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.     

Preparation and evaluation of ibuprofen-loaded microemulsion for improvement of oral bioavailability

The purpose of the current study was to improve the solubility of ibuprofen, a poorly water-soluble drug, in a microemulsion system that is suitable for oral administration. Microemulsion was prepared using different sorts of oils, surfactants, and co-surfactants. Pseudo-ternary phase diagrams were used to evaluate the microemulsion domain. The formulations were characterized by solubility of the drug in the vehicle, droplet size, and drug release. The optimal formulation consists of 17% Labrafil M 1944CS, 28% Cremophor RH40/Transcutol P (3:1, w/w), and 55% water, with a maximum solubility of ibuprofen up to 60.3?mg/ml. The mean droplet size of microemulsion was 57?nm. The pharmacokinetic study of microemulsion was performed in rats and compared with granule formulation. The microemulsion has significantly increased the C_max and area under the curve (AUC) compared to that of the granule (p?<?0.05). The relative bioavailability of ibuprofen in microemulsions was 1.9-fold higher than that of the granule. These results indicated that this novel microemulsion is a useful formulation for enhancing the oral bioavailability of ibuprofen.     

Input rate-dependent stereoselective pharmacokinetics: enantiomeric oral bioavailability and blood concentration ratios after constant oral input.

A pharmacokinetic model and relevant equations were used to simulate the blood concentration ratio (Cratio) and oral bioavailability ratio (Fratio) of the two enantiomers of model racemic drugs after different oral input rates. The simulations were carried out for six metabolically eliminated racemic drugs with regard to differences between the two enantiomers in their metabolic maximum velocity (Vmax) and/or Michaelis-Menten constant (Km). Both Cratio and Fratio values were dependent on the oral input rate of the drugs, with the maximum sensitivity observed for input rates close to the Vmax of the enantiomers. However, at input rates substantially lower or higher than Vmax, the dependence of ratios to input rate was minimal. The profile of dependence of Cratio and Fratio on the input rate differed for the various modeled drugs and, in one case, input rate alteration lead to a reversal in the stereoselectivity of the ratios. Relevance of these findings with regard to alterations in the dose and/or formulation of racemic drugs is discussed.