Prediction of human absorption of a trioxane antimalarial drug (CDRI 99/411) using an in-house validated in situ single-pass intestinal perfusion model
Wahajuddin,
Sheelendra Pratap Singh
1
Pharmacokinetics and Metabolism Division, Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow, Uttar Pradesh, India
,
Kushalkumar Patel
2
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Rae Bareli, India
,
Tejaswini Pradhan
1
Pharmacokinetics and Metabolism Division, Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow, Uttar Pradesh, India
,
Hefazat Hussain Siddiqui
3
Faculty of Pharmacy, Integral University, Lucknow, India
,
Shio Kumar Singh
1
Pharmacokinetics and Metabolism Division, Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow, Uttar Pradesh, India
The aim of the study was to predict human intestinal permeability and the fraction absorbed of an oral dose of a promising trioxane anti-malarial drug (CDRI 99/411) using the single-pass intestinal perfusion technique (SPIP) in rats.
Methods:
Effective permeability coefficients (Peff) in anaesthetized rats were determined for marker compounds and the trioxane derivative 99/411. Drug solution in perfusion buffer was perfused through intestine with a flow rate of 0.2 ml/min and samples were taken from an outlet tubing at different time points up to 120 min. Drug concentrations in samples were determined using RP-HPLC.
Key findings:
The effective permeability coefficient values of marker compounds obtained in rats were compared with published data for human intestinal permeability (Peff(human)) and human fraction absorbed (Fa (human)) to establish an in-house model. Strong correlations were found between rat and human values for markers (Peff(human) = 1.039 Peff(rat) −0.1815; R2= 0.970 and Fa (human) = 0.1562ln (Peff(rat)) + 0.7232; R2 = 0.927). Subsequently the human permeability and fraction dose absorbed in human were predicted for 99/411 using the obtained rat permeability value and established correlations. Peff in human predicted from the model was found to be 7.05 × 10−4 cm/s and Fa value in human was predicted around 1.
Conclusions:
Considering the high correlation of rat Peff values with those of human reported values, it can be concluded that the developed in-house model is reliable and can be used preliminarily, to predict human permeability and fraction dose absorbed of any test compound. From predicted results, 99/411 was found to have high permeability and possibly complete absorption in human.
Key words
Antimalarial drug -
CDRI 99/411 -
Human absorption -
In situ permeability -
Trioxane
References
1 Prentis RA, Lis Y, Walker SR. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). Br J Clin Pharmacol. 1988; 25: 387-96
2 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46: 3-26
3 Shantha Kumar TR, Chawla S, Nachaegari SK, Singh SK, Srinivas NR. Validated HPLC analytical method with programmed wavelength UV detection for simultaneous determination of DRF-4367 and phenol red in rat in situ intestinal perfusion study. J Pharm Biomed Anal. 2005; 38: 173-9
4 Chawla S, Ghosh S, Sihorkar V, Nellore R, Kumar TR, Srinivas NR. High-performance liquid chromatography method development and validation for simultaneous determination of five model compounds, antipyrine, metoprolol, ke-toprofen, furosemide and phenol red, as a tool for the standardization of rat in situ intestinal permeability studies using timed wavelength detection. Biomed Chromatogr. 2006; 20: 349-57
5 Zakeri-Milani P, Valizadeh H, Tajerzadeh H, Azarmi Y, Is-lambolchilar Z, Barzegar S et al. Predicting human intestinal permeability using single-pass intestinal perfusion in rat. J Pharm Pharm Sci. 2007; 10: 368-79
6 Salphati L, Childers K, Pan L, Tsutsui K, Takahashi L. Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man. J Pharm Pharmacol. 2001; 53: 1007-13
8 Papadopoulou V, Valsami G, Dokoumetzidis A, Macheras P. Biopharmaceutics classification systems for new molecular entities (BCS-NMEs) and marketed drugs (BCS-MD): theoretical basis and practical examples. Int J Pharm. 2008; 361: 70-77
9 Cook J, Addicks W, Wu YH. Application of the biopharma-ceutical classification system in clinical drug development-an industrial view. AAPS J. 2008; 10: 306-10
10 Kim JS, Mitchell S, Kijek P, Tsume Y, Hilfinger J, Amidon GL. The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Mol Pharm. 2006; 3: 686-94
12 Singh RP, Sabarinath S, Singh SK, Gupta RC. A sensitive and selective liquid chromatographic tandem mass spec-trometric assay for simultaneous quantification of novel trioxane antimalarials in different biomatrices using sample-pooling approach for high throughput pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 864: 52-60
13 Varma MV, Panchagnula R. Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeabilityin vitro, in situ and in vivo. Eur J Pharm Sci. 2005; 25: 445-53
14 Komiya I, Park JY, Kamani A, Ho NFH, Higuchi WI. Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int J Pharm. 1980; 4: 249-62
15 Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2004; 1: 85-96
