[Measurement of plasma concentration and bioavailability of nolatrexed dihydrochloride in mice].
OBJECTIVE
To establish a methods based on high-performance liquid chromatogram-mass spectrum for measuring the plasma concentration of nolatrexed dihydrochloride and investigate the pharmacokinetic profile and absolute bioavailability of the drug in mice.


METHODS
Nolatrexed dihydrochloride were injected intravenously at 50 mg/kg or administered orally at 200 mg/kg in mice, and blood samples were collected at various time points following drug administration. The plasma concentration of nolatrexed dihydrochloride in mice was determined using high-performance liquid chromatogram-mass spectrum. The pharmacokinetic parameters were calculated using DAS software, and the absolute bioavailability of orally and intravenously administered was assessed according to the ratio of their area under the curve (AUC).


RESULTS
The method showed good linear relationship within the drug concentration range of 0.01-40 mg/L (r=0.9995, P<0.001). The recovery of nolatrexed dihydrochloride from the mouse plasma was more than 85%, and the intra- and inter-day precision expressed as the relative standard deviation was less than 15%. The half-life (T(1/2)), AUC, distribution factor and plasma clearance (CL) for intravenously administered nolatrexed dihydrochloride (50 mg/kg) were 3.020-/+0.017 h, 89.972-/+0.425 mg/L/h, 0.831-/+0.106 L/kg, and 0.556-/+0.093 L/h/kg, respectively. The T(1/2), AUC, peak time (T(max)) and peak concentration (C(max)) for orally administered drug were 5.046-/+0.191 h, 84.893-/+9.923 mg/L/h, 1.000-/+0.012 h, and 18.000-/+0.0140 mg/L, respectively. The absolute bioavailability of nolatrexed dihydrochloride in mice was 23.58%.


CONCLUSIONS
The absolute bioavailability of nolatrexed dihydrochloride in mice determined in this study provides an experimental basis for development of the oral preparation of the drug.
Wang
Guang-Fa
GF
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Zhang
Jun-Yan
JY
Wu
Shao-Yu
SY
Xu
Wei
W
Wan
Shan-He
SH
Shao
Cai-Feng
CF
Zhang
Jia-Jie
JJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000097:blood* / Q000493:pharmacokinetics*
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; C099178:nolatrexed