Development and validation of an enantioselective LC-MS/MS method to quantify enantiomers of (±)-TAK-700 in rat plasma: lack of in vivo inversion of (+)-TAK-700 (Orteronel) to its antipode.
A highly sensitive, specific and enantioselective assay has been developed and validated for the estimation of TAK-700 enantiomers [(+)-TAK-700 and (-)-TAK-700] in rat plasma on LC-MS/MS-ESI in the positive-ion mode. Liquid-liquid extraction was used to extract (±)-TAK-700 enantiomers and IS (phenacetin) from rat plasma. TAK-700 enantiomers were separated using methanol and 5 mm ammonium acetate (80:20, v/v) at a flow rate of 0.7 mL/min on a Chiralcel OJ-RH column. The total run time was 7.0 min and the elution of (+)-TAK-700, (-)-TAK-700 and IS occurred at 3.71, 4.45 and 4.33 min, respectively. The MS/MS ion transitions monitored were m/z 308.2 → 95.0 for TAK-700 and m/z 180.2 → 110.1 for IS. The standard curves for TAK-700 enantiomers were linear (r(2) > 0.998) in the concentration range 2.01-2015 ng/mL for each enantiomer. The inter- and intra-day precisions were in the ranges 3.74-7.61 and 2.06-8.71% and 3.59-9.00 and 2.32-11.0% for (+)-TAK-700 and (-)-TAK-700, respectively. Both the enantiomers were found to be stable in a battery of stability studies. This novel method was applied to the study of stereoselective oral pharmacokinetics of (+)-TAK-700 and it was unequivocally demonstrated that (+)-TAK-700 does not undergo chiral inversion to its antipode in vivo.
Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, India.
Sandip
S
Gurav
Anitha
A
Police
Mohd
M
Zainuddin
Ravindra Ramachandra
RR
Punde
Purushottam
P
Dewang
V
V
Chandregowda
Raghava Reddy
RR
Kethiri
Sriram
S
Rajagopal
Ramesh
R
Mullangi
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D007093:Imidazoles / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D009281:Naphthalenes / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*
D007093:Imidazoles; D009281:Naphthalenes; C571806:orteronel