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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Acknowledgement
 »  References
 »  Article Figures
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 Table of Contents    
RESEARCH ARTICLE
Year : 2012  |  Volume : 44  |  Issue : 1  |  Page : 57-62
 

Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone


1 Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, Uttar Pradesh, India
2 Biochemistry Division, Central Drug Research Institute, CSIR, Lucknow, Uttar Pradesh, India
3 Medicinal and Process Chemistry, Central Drug Research Institute, CSIR, Lucknow, Uttar Pradesh, India

Date of Submission30-Apr-2011
Date of Decision25-May-2011
Date of Acceptance18-Oct-2011
Date of Web Publication14-Jan-2012

Correspondence Address:
Rabi S Bhatta
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, Uttar Pradesh
India
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Source of Support: Central Drug Research Institute, Lucknow India., Conflict of Interest: None


DOI: 10.4103/0253-7613.91868

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 » Abstract 

Objectives: To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP).
Materials and Methods: The disposition of DHP following oral (36, 72, 100 and 150 mg/kg) and intravenous (1, 5 and 10 mg/kg) administration and its dose-response relationship were carried out in Sprague-Dawley rats. DHP and its metabolite 5-pregnene-3β-ol-16, 17-epoxy-20-one (M1) were analyzed by a validated LC-MS/MS method in plasma after intravenous and oral administration. Dose escalation lipid lowering activities were carried out by triton-induced hyperlipidemic model.
Results: Oral administration resulted in higher amount of M1 formation as compared to intravenous administration. Dose escalation intravenous administration (1, 5 and 10 mg/kg) resulted in nonlinear increase in AUC of DHP. This was due to saturation of metabolism. On the contrary, systemic AUC and C max after oral administration show non-linear pharmacokinetics where saturated systemic DHP and M1 pharmacokinetics was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg. Conclusion: DHP exhibits route and dose-dependent pharmacokinetics. Pharmacokinetic and lipid lowering activity by oral route indicate saturation of oral absorption at higher doses. The study contributes to the understanding of the plasma disposition pharmacokinetics of DHP and its metabolite in rats by oral and intravenous route of administration.


Keywords: Dose-escalation pharmacokinetics, lipid-lowering activity, 80/574


How to cite this article:
Kumar D, Khanna AK, Pratap R, Sexana JK, Bhatta RS. Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone. Indian J Pharmacol 2012;44:57-62

How to cite this URL:
Kumar D, Khanna AK, Pratap R, Sexana JK, Bhatta RS. Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone. Indian J Pharmacol [serial online] 2012 [cited 2021 Mar 7];44:57-62. Available from: https://www.ijp-online.com/text.asp?2012/44/1/57/91868



 » Introduction Top


16-Dehydropregnenolone (DHP, 80/574) [Figure 1] was developed by Central Drug Research Institute (CDRI) as an antihyperlipidemic agent. It has shown significant lipid lowering activity in preclinical [1],[2] and clinical studies. Presently it is inphase-III clinical trial. [3] It acts as a farnesoid X receptor antagonist, a nuclear hormone receptor that is activated by bile acids. [4] DHP increases high density lipoprotein (HDL) levels, inhibits platelet aggregation and decreases the cholesterol biosynthesis in liver. DHP also demonstrates a marked antioxidant activity in experimental models, prevents the oxidation of low density lipoprotein (LDL) and thus, may provide a protection against atherogenesis. Chronic toxicity studies indicate that this drug is free from untoward effects and possesses a good therapeutic window. [1],[2]
Figure 1: Structure of 16-dehydropregnenalone (a) and its metabolite epoxy-DHP (M1)(b)

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Pilot studies on pharmacokinetics of DHP have been reported. [5] However, its dose proportionality pharmacokinetics and oral hypolipidemic activity have not been reported. The purpose of the present study is, therefore, to investigate the dose ranging pharmacokinetics of DHP and its metabolite (M1) by oral and intravenous(i.v.) administration and lipid lowering activity in rats. The present study also evaluates the extent of DHP metabolism in relation to route and dose.


 » Materials and Methods Top


16-Dehydropregnenolone (DHP) was synthesized at Medicinal and Process Chemistry Division, CDRI, India. 5-pregnene-3β-ol-16,17-epoxy-20-one (M1) was synthesized at the Pharmacokinetic and Metabolism division. NN-dimethyl acetamide, polyethyleneglycol (PEG-400), carboxymethylcellulose and dexamethasone were purchased from Sigma Aldrich (St. Louis, MO). Heparin sodium injection IP (Beparine® , 5000 IU/ml, Biological E, Hyderabad, India) was locally purchased. All other solvents and reagents were of analytical or HPLC grade.

Formulation

(a) Suspension

0The DHP suspension was prepared prior to administration by using carboxymethyl cellulose (0.5%w/v) as suspending agent. Pharmacokinetic and hypolipidemic studies were carried out at 36, 72, 100 and 150 mg/kg oral dose. The formulation was administered by 20G gavage needle.

(b) Intravenous

Intravenous (i.v.) administration of DHP was carried out at three doses (1, 5 and 10 mg/kg). Intravenous formulation was prepared by dissolving required quantity of DHP and hydroxypropyl-β-cyclodextrin(HP-β-CD) at 1:1 molar ratio in sterile saline. The formulation was filtered through 0.22 μm sterile membrane filter. The ratio of DHP and HP-β-CD was constant for all i.v. formulations. The final amount of HP- β-CD was less than 5.4% w/v. Aseptic procedure was followed during preparation. Formulation was prepared just prior to administration into the tail vein.

Pharmacokinetic study

Male Sprague-Dawley rats (220 ± 20 g) were obtained from National Laboratory Animal Centre, CDRI, Lucknow, India. Animals were maintained according to the standard housing conditions and given a pellet diet (Lipton India Ltd., Bangalore) and water. The rats were acclimatized for three days before experiment. All experiments were done in triplicate.

The rats were fasted overnight before dosing with free access to water. Food was provided ~2 h post oral dose. DHP at 36, 72, 100 and 150 mg/kg as aqueous suspension was administered. Blood samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h post dose in heparinized tubes (22 IU per ml blood). Intravenous pharmacokinetics was carried out at a dose of 1, 5 and 10 mg/kg i.v. Blood samples were collected at 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h post dose in heparinized tubes. In order to keep the total volume of blood withdrawn during 24 h to be< 5% of the blood volume, the samples were collected by sparse sampling technique with not more than three blood samples from each rat. [6],[7] Samples were collected from each rat in the study group, by cardiac puncture (~0.5 ml) followed by terminal sampling from inferior vena cava under light anesthesia. Blood samples were centrifuged at 2000 g for 10 min and plasma was separated and stored at -60°C until analysis. All experimental procedures were in accordance with the guidelines laid down by local institutional ethics committee for experimental animal. DHP and its major metabolite M1 (5-pregnene-3β-ol-16, 17-epoxy-20-one) were analyzed by LC-MS/MS method, reported earlier. [5] The accuracy and precision were within the limit as per FDA guidelines. Pharmacokinetic parameters were calculated by WinNonlin software ver. 5.1 (Scientific Consultant Inc) by non-compartmental modeling approach.

Fecal Excretion Study

Fecal excretion study was carried out on male Sprague-Dawley rats (220 ± 20g). Rats were acclimatized for three days prior to study. DHP at a dose of 100 mg/kg as aqueous suspension was administered orally. Fecal samples were collected at 0-6 h, 6-12 h, and 12-24 h. These were dried and powdered. DHP and its metabolite M1 were analyzed by the LC-MS/MS method validated earlier with slight modification. Briefly, calibration standard, quality control and test samples were prepared by extraction with acetonitrile. The blank fecal suspension was prepared by adding 50 mg of dried feces to 100 μl water and incubated for 10 min. Calibration standard and quality control samples were prepared in 100 μl blank fecal aqueous suspension. The corresponding working stock solution (10 μl) of DHP and M1 was added to each tube to get a concentration range from 1.56 to 200 ng/ml. To each tube 20 μl of 5 μg/ml (dexamethasone) working stock was added as internal standard (IS). QC samples of five replicates at each concentration level of 1.56 ng/ml (lower limit of quantitation, LLOQ), 3.12 ng/ml (QC low), 50 ng/ml (QC medium) and 200 ng/ml (QC high) were prepared. Dried fecal samples of 50 mg was hydrated in 100 μl water and incubated for 10 min in room temperature. The standards and samples were extracted by adding 1 ml acetonitrile. The extraction tubes were vortexed for 2 min and centrifuged at 12000 × g for 20 min. Supernatant was evaporated under reduced pressure. The dried residue was reconstituted in 100 μl of reconstitution solvent (acetonitrile) and 20 μl was injected onto the LC-MS/MS system.

Lipid Lowering Activity

Efficacy study was carried out using Triton model of hyperlipemia. [8] Rats weighing 200±20 g were divided into (i) control, (ii) triton and (iii) triton + drug treated groups(n=6 in each group). Triton WR-1339 was administered (400 mg/kg) by intraperitoneal injection to all groups. Treated group received the drug and control received saline. Blood was collected after 18 h and serum cholesterol, triglyceride and phospholipids were estimated and expressed as percent reduction with reference to control. [9] Dose escalation lipid lowering activity was carried out at the doses of 36, 72, 100 and 150 mg/kg of oral suspension. Dose-response modeling was carried out with WinNonlin software Ver 5.1 bysigmoidor Emax model to calculate Emax and EC50.

Data Analysis

The mean concentration time profile of DHP and its metabolite M1 were subjected to non-compartmental model analyses using WinNonlin software 5.1 (Scientific Consultant Inc) to calculate pharmacokinetic parameters. Maximum concentration in plasma (C max ) and time to achieve it (T max ) were noted directly from plasma concentration- time profile. The elimination rate constant (Kel) was calculated from the slope of the terminal phase of the plasma concentration - time plot considering at least three data points. t 1/2 was calculated by t 1/2= ln (2) / λZ , where λZ is the elimination rate constant. Mean residence time (MRT) was calculated by dividing area under the first moment curve (AUMC 0-24 ) by AUC 0-24 . AUC 0-∞ was calculated by linear trapezoid method with extrapolation to infinity calculated by concentration of last time point divided by terminal rate constant. AUC 0-24 ± SD was calculated using the method of Bailer. [10] Clearance was calculated by Cl = F X Dose / AUC 0-∞ and Vd= F X Dose / λZ AUC 0-∞, where F was calculated from intravenous pharmacokinetic data. The percent of metabolite observation was calculated as percent of AUC of metabolite to that of AUC of parent. The differences between mean values were analyzed for significance using analysis of variance (ANOVA) followed by Newmann-Keules multiple comparison tests. The results were considered as statistically significant at P<0.05.


 » Results Top


The mean plasma concentration time profiles of intravenous and oral administration are illustrated in [Figure 2]. The pharmacokinetic parameters of DHP and M1 are summarized in [Table 1] and [Table 2].
Figure 2: Plasma concentration of 16-dehydropregnenolone (DHP) and its metabolite M1 after oral (a, b) and intravenous administration (c, d). Arrows denote multiple peaks

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Table 1: Pharmacokinetics of 16-dehydropregnenolone after intravenous and oral administration

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Table 2: Pharmacokinetic parameters of metabolite M1 after oral and intravenous administration of 16-dehydropregnenolone (DHP)

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Oral Pharmacokinetics

Oral pharmacokinetics of DHP was performed at doses of 36, 72, 100 and 150 mg/kg administered as aqueous suspension. Multiple peaks were observed at ~0.25, ~1.5, ~4, ~7-8 h post dose in both DHP and M1 plasma concentration profile. Increasing oral dose of DHP from 36 to 72 mg/kg also increased the AUC 0-24, t 1/2 and C max by ~3.3, ~2.5 and ~2.5 fold respectively. However, a twofold increment in dose above 72 mg/kg did not result in proportional increase which indicates the saturation of pharmacokinetic parameters. The volume of distribution was increased by two fold with increase in dose from 36 to 72 mg/kg and thereafter no further increment was observed. Oral pharmacokinetics exhibited increment in MRT in the ratio of 1: 1.5: 3: 2.6 for the doses of 36, 72, 100 and 150 mg/kg DHP respectively. Thus residence period of DHP in the body increased with the increasing dose. No significant difference in C max of M1 was observed upon oral dose escalation from 36 to 150 mg/kg. The AUC of M1 increased significantly on increasing the dose from 36 to 150 mg/kg. MRT of M1 was increased in the ratio of 1: 1.5: 2: 4.4 with dose 36, 72, 100 and 150 mg/kg DHP oral administration respectively. The ratio of AUC parent/AUC metabolite (AUC p /AUC m ) reached saturation after 72 mg/kg [Figure 3].
Figure 3: Dose escalation pharmacokinetics of 16-dehydropregnenolone (DHP) and its metabolite M1 after oral (A, C) and intravenous (B, D) administration

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Bioavailability exhibited a decreasing trend on increasing the dose from 72 to 150 mg/kg [Table 1]. To understand the reason for this decreasing bioavailability, fecal excretion study was carried out. It estimated the excretion of 42.23 ± 12.23% of DHP in feces. Metabolite M1was not found in feces.

Intravenous Administration

Intravenous dose escalation pharmacokinetics was performed at doses of 1, 5 and 10 mg/kg of DHP. Multiple peaks were observed at ~0.75, ~1.5-2 and ~3-4 h post dose in both DHP and M1 plasma concentration profile at all doses. Increasing i.v. dose from 1 to 10 mg/kg resulted in two fold increase in dose normalized AUC and clearance was reduced by two fold with 10 fold increase in i.v. dose. Clearance decrease resulted in increased terminal elimination half-life at 10 mg/kg (t ½ = 2.3 hr) as compared to 1 mg/kg (t 1/2 = 1.6 hr). MRT was also increased by two fold. However, MRT of 10 mg/kg was less than t 1/2 . This type of observation has been reported earlier in literature. [11]

Metabolite M1 was observed at 5 and 10 mg/kg i.v. doses; however, highest concentration was reached at ~0.25 h. This exhibited lag phase in metabolite formation. Thus by parenteral administration there was a delay in DHP reaching to the probable site of M1formation. This may be the reason for absence of M1 at low i.v. dose (1 mg/kg DHP), as DHP may not have reached the site of M1 formation in a sufficient amount (low concentration gradient for diffusion) to produce detectable amount of metabolite. The AUC p /AUC m was higher at i.v. as compared to the oral administration, which indicates an extensive metabolism in gastro-intestinal tract (GIT).

C max of M1 by i.v. administration at 5 mg/kg was significantly lower as compared to 10 mg/kg but AUCs were not significantly different [Table 2]. The ratio of AUC p /AUC m was also in increasing trend. This suggests saturation of metabolite formation which resulted in increased amount of DHP escape metabolism, whereas in case of oral administration the ratio reached the saturation after 72 mg/kg only. The non-linearity was due to the saturation in amount of absorbed DHP and so was the formation of M1. Thus the resultant ratio of AUC p /AUC m above 72 mg/kg dose was relatively constant [Figure 3]. The lipid lowering activity exhibited saturation above 72 mg/kg. This activity was not observed below 36 mg/kg p.o [Table 3].
Table 3: Lipid lowering activity of 16-dehydropregnenolone administered as oral suspension

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 » Discussion Top


Route of administration as well as formulation are important in pharmacokinetic profiling of new chemical entities (NCE). Suspension is a preferred formulation to generate preliminary oral pharmacokinetics of water insoluble drug as it is devoid of surfactant, which is known to alter physiology of GI tract and modulate pharmacokinetic parameters. Absorption of a drug from suspension depends upon its intrinsic permeability and solubility (as only soluble fraction gets absorbed). Conversely absorption phase is absent after i.v. administration. Thus a comparative oral and i.v. pharmacokinetics was studied for both the DHP and its metabolite M1. Intravenous formulation was prepared by dissolving DHP in HP-β-CD at a molar ratio of 1:1 complex, which resulted in higher solubility and ensure that the drug will not precipitate even if concentration of drug exceeds its water solubility. [12] HP-β-CD is one of the excipients safely administered by parental route. [13]

Plasma concentration profile exhibited multiple-peak phenomenon. Generally the mechanisms proposed to explain multiple peaks include entrohepatic recirculation, selective and differential absorption from GIT (absorption window), and variation in gastrointestinal motility and gastric emptying. [14],[15] In case of oral administration, initial peak plasma concentration [Figure 2]A at ~15 min may be due to rapid absorption of soluble DHP (burst effect), followed by depletion and slow absorption having a second highest C max at 1.5 h. Plasma concentration profile (DHP) of suspension at 36, 72, 100 and 150 mg/kg [Figure 2]A shows distinct peak at ~ 4 h. Rat intestinal transit time is about ~88 min. [16] Thus this was the minimum time needed for de-conjugation of drug from the bile/conjugated metabolite by the intestinal microbes, so as to get the free drug for absorption. Peak plasma concentration of DHP and M1 after ~88 min may be due to the entrohepatic recirculation (EHC). The cyclic appearance of DHP and M1 in peak plasma concentration (~1.5, ~4, ~8 h) at elimination phase was observed. It also indicates enterohepatic recirculation (EHC) and eliminates the possibility of absorption window.

Further, to rule out the possibility of other GI factors, DHP was administered by i.v. route also. Presence of multiple peaks in plasma concentration profile by oral and i.v. administration at definite intervals(1.5-3 h and 3-5 h) indicates presence of EHC. [14],[17] Thus pharmacokinetics by oral and i.v. route of administration confirmed the EHC of both DHP and M1. Similar PK profile of parent drug and its metabolite has earlier been reported with valproic acid known to undergo EHC. [18]

Non-linear pharmacokinetics was observed after oral administration of DHP. Clearance was not altered and PK parameters such as C max and AUC reached saturation above 72 mg/kg. MRT increased ~three fold from 36 to 150 mg/kg. This may be because of the limited GI absorption from suspension. This was further confirmed by saturation of AUC of M1 and ratio of AUC p /AUC m . The non linearity was due to saturation in amount of absorbed DHP and the formation of M1. This may also be due to the poor aqueous solubility (~3 μg/ml) of DHP. Blood levels of DHP indicate its rapid absorption which is also dissolution rate limiting. Oral dose escalation pharmacokinetics also corroborated with the lipid lowering activity of the molecule wherein the activity did not increase above 72 mg/kg. In case of i.v. administration, ratio of AUC p /AUC m showed an increasing trend. This may be due to the saturation of metabolism rate which may have resulted in higher amount of DHP escape metabolism. This was also reflected in reduced clearance.

With the increasing i.v. dose, decreasing trend in clearance was observed. This observation is similar to the oral administration where also a decreasing trend of clearance was observed with increasing dose. Volume of distribution was higher than rat blood volume which indicates a rapid and extensive distribution to peripheral compartment. [16]

In conclusion, dose-dependent pharmacokinetics of DHP was observed at doses 36 to 150 mg/kg oral and 1 to 10 mg/kg i.v. in male rats since AUC values appeared to be disproportional with dose escalation. With the increasing dose i.v. the AUC was increased exponentially and clearance was decreased, whereas in case of oral administration systemic AUC reached saturation after a dose of 72 mg/kg. It may be due to dissolution limited absorption of DHP. The formation of metabolite M1 was also route dependent and GI track was the main site of formation. DHP and M1 by both oral and i.v. administration show multiple-peak phenomenon, indicating EHC of DHP. Lipid lowering activity of DHP by its oral route was in accordance with its pharmacokinetics and the activity reached saturation above 72 mg/kg. The results of this study contribute to the understanding of the plasma disposition pharmacokinetics of DHP in Sprague-Dawley rats.


 » Acknowledgement Top


The authors are thankful to Director, Central Drug Research Institute, Lucknow, India, for his constant encouragement and support. Authors acknowledge Dr. G. K. Jain for his valuable suggestion and support. We also acknowledge Council of scientific and industrial Research (CSIR) for providing research fellowships to one of the authors.

 
 » References Top

1.Pratap R,Gupta RC, Chander R, Khanna AK, Srivastava AK, Raina D, et al. Method of treating hyperlipidemic and hyperglycemic conditions in mammals using pregnadienols and pregnadienones Patent no 6,875,758, 1999.  Back to cited text no. 1
    
2.Pratap R, Gupta RC, Chander R, Khanna AK, Srivastava AK, Raina D, et al. Method of treating hyperlipidemic and hyperglycemic conditions in mammals using pregnadienols and pregnadienones Patent no. 99302556.8, 1999.  Back to cited text no. 2
    
3.CDRI Annual Report 2006-07. Lucknow: Central Drug Research Institute; 2007.  Back to cited text no. 3
    
4.Wu J, Xia C, Meier J, Li S, Hu X, Lala DS. The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor. Mol Endocrinol 2002;16:1590-7.  Back to cited text no. 4
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5.Suryawanshi S, Singh SK, Gupta RC. A sensitive and selective HPLC/ESI-MS/MS assay for the simultaneous quantification of 16-dehydropregnenolone and its major metabolites in rabbit plasma. J Chromatogr B 2006;830:54-63.  Back to cited text no. 5
    
6.Sabarinath S, Madhusudanan KP, Gupta RC. Pharmacokinetics of the diastereomers of arteether, a potent antimalarial drug, in rats. Biopharm Drug Dispos 2005;26:211-23.  Back to cited text no. 6
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7.Jia L, Noker PE, Coward L, Gorman GS, Protopopova M, Tomaszewski JE. Interspecies pharmacokinetics and in vitro metabolism of SQ109. Br J Pharmacol 2006;147:476-85.  Back to cited text no. 7
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8.Tamasi G, Borsy J, Patthy A. Comparison of the antilipemic effect of nicotinic acid (NA) and 3-methylpyrazole-5-carboxylic acid (MPC) in rats. Biochem Pharmacol 1968;17:1789-94.  Back to cited text no. 8
    
9.Batra S, Srivastava S, Singh K, Chander R, Khanna AK, Bhaduri AP. Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents. Bioorg Med Chem 2000;8:2195-209.  Back to cited text no. 9
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10.Bailer AJ. Testing for the equality of area under the curves when using destructive measurement techniques. J Pharmacokinet Biopharm 1988;16:303-9.  Back to cited text no. 10
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11.Eyal S, Meir B. The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body model. Biopharm Drug Dispos 2004;25:157-62.  Back to cited text no. 11
    
12.Zuo Z, Kwon G, Stevenson B, Diakur J, Li W. Flutamide-hydroxypropy-beta-cyclodextrin complex: Formulation, physical characterization, and absorption studies using the Caco-2 in vitro model. J Pharm Pharm Sci 2000;3:220-7.  Back to cited text no. 12
    
13.Kim JH, Lee SK, Ki MH, Choi WK, Ahn SK, Shin HJ, et al. Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-beta-cyclodextrin. Int J Pharm 2004;272:79-89.  Back to cited text no. 13
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14.Wang Y, Roy A, Sun L, Lau CE. Short communication: A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos 1999;27:855-9.  Back to cited text no. 14
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15.Shim CK, Suh MK. Multiple plasma peaks of acetaminophen and ranitidine after simultaneous oral administration to rats. Arch Pharm Res 1992;15:246-50.  Back to cited text no. 15
    
16.Brian D, Tim M. Physiological parameters in laboratory animals and humans. Pharm Res 1993;10:1093-5.  Back to cited text no. 16
    
17.Sargel L. Applied biopharmaceutical and pharmaceutics. 4 th ed. London: Prenitice-Hall International; 1999.  Back to cited text no. 17
    
18.Dickinson RG, Harland RC, Ilias AM, Rodgers RM, Kaufman SN, Lynn RK, et al. Disposition of valproic acid in the rat: Dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect. J Pharmacol Exp Ther 1979;211:583-95.  Back to cited text no. 18
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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