Prediction of human absorption of a trioxane antimalarial drug (CDRI 99/411) using an in-house validated in situ single-pass intestinal perfusion model.
OBJECTIVE
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 (P eff) 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.


RESULTS
The effective permeability coefficient values of marker compounds obtained in rats were compared with published data for human intestinal permeability (P eff (human)) and human fraction absorbed (F(a) (human)) to establish an in-house model. Strong correlations were found between rat and human values for markers (P eff (human) = 1.039 P eff (rat) - 0.1815; R2 = 0.970 and F(a) (human) = 0.15621n (P eff (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. P eff in human predicted from the model was found to be 7.05 x 10(-4) cm/s and F(a) 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.
Pharmacokinetics and Metabolism Division, Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow, Uttar Pradesh, India. wahajuddin@cdri.res.in
Wahajuddin
Sheelendra Pratap
SP
Singh
Kushalkumar
K
Patel
Tejaswini
T
Pradhan
Hefazat Hussain
HH
Siddiqui
Shio Kumar
SK
Singh
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics*; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D010539:Permeability; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions; D013141:Spiro Compounds / Q000493:pharmacokinetics*
C529215:99-411 compound; D000962:Antimalarials; D002021:Buffers; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D012996:Solutions; D013141:Spiro Compounds