title: Pharmacokinetics and brain uptake of HIV-1 replication inhibitor DB213 in Sprague-Dawley rats.
abstract: The current study aims to investigate the pharmacokinetics and brain uptake of HIV-1 replication inhibitor DB213 via a developed LC/MS/MS analytical method. A sensitive, selective, accurate and reliable LC/MS/MS method for determination and quantification of DB213 in rat plasma and brain was developed and validated. A triple quadrupole mass spectrometer equipped with electrospray ionization (ESI) source was applied for the detection of DB213 and benzamidine (Internal Standard). The analytes were quantified by using multiple reaction monitoring (MRM) mode with m/z 333.4→86.1 and m/z 121.2→104 for DB213 and benzamidine respectively. Chromatographic separation of DB213 and benzamidine was achieved on a SunFire C8 (4.6×250mm, i.d. 5μm) analytical column with gradient elution of a mobile phase consisted of acetonitrile and 20mM ammonium formate buffer (containing 0.5% formic acid). The method achieved good linearity from 1.95∼1000ng/ml (r(2)=0.999) in plasma and 0.98∼125ng/ml (r(2)=0.999) in brain. The validated method was successfully applied to plasma pharmacokinetics (PK) and brain uptake of intravenous administration of DB213 water solution (1mg/kg) to Sprague-Dawley rats. It was found that the area under the plasma concentration-time curve from 0 to 360min (AUC0→360min) was 184422.1±42450.8ngmin/ml and the elimination half-life of DB213 after intravenous administration was 70.9±16.1min. In addition, DB213 has demonstrated a potential to cross the blood-brain barrier via intravenous administration with a brain tissue concentration of 11.3±3.6ng/g peaked at 30min post-dosing.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Qianwen
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Peng
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Wong
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: H Y Edwin
authors.initials: HY
authors.lastname: Chan
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. Electronic address: joanzuo@cuhk.edu.hk.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001550:Benzamidines / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D057230:Limit of Detection; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D001550:Benzamidines; C000618313:DB213 compound
keywords: Brain uptake; DB213; LC/MS/MS; Plasma pharmacokinetics