NDLI: Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method

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Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method

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Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method

Content Provider	Springer Nature Link
Author	Chen, Chun Lin Uckun, Fatih M.
Copyright Year	1999
Abstract	Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t$_{1/2ka}$ and a t$_{max}$ values of less than 10 min. Following oral administration, HI-240 was absorbed with a t$_{1/2ka}$ of 4.2 ±1.1 min and a t$_{max}$ of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
Starting Page	1226
Ending Page	1232
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	16
Issue Number	8
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	1999-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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In vivo Toxicity, Pharmacokinetic Features and Tissue Distribution of N-[2-(2,5-Dimethoxyphenylethyl)]-N’-[2-(5-bromopyridyl)]-thiourea (HI-236), a Potent Non-nucleoside Inhibitor of HIV-1 Reverse Transcriptase

N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (HI-443), a Rationally Designed Non-Nucleoside Reverse Transcriptase Inhibitor Compound with Potent Anti-HIV Activity

In vivo Pharmacokinetics and Toxicity of a Novel Hydrophilic Oral Formulation of the Potent Non-Nucleoside Reverse Transcriptase Inhibitor Compound N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443)

In vivo Pharmacokinetics, Metabolism, Toxicity, and Anti-HIV Activity of N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (HI-443), a Potent Non-nucleoside Inhibitor of HIV Reverse Transcriptase

Large-scale Synthesis of GMP Grade N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443), a New Anti-HIV Drug Candidate

Improved Oral Bioavailability of Anti-HIV Agent N'-[2-(2-Thiophene)ethyl]-NT-[2-(5-bromopyridyl)]-thiourea (HI-443) in a Novel Lipophilic Formulation

A novel vaginal microbicide containing the rationally designed anti-HIV compound HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]).

Investigation of the solvent-dependent photolysis of a nonnucleoside reverse-transcriptase inhibitor, antiviral agent efavirenz

SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method

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