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Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxyethyl)adenine
L Naesens1, J Balzarini, E De Clercq
1Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Abstract:
The pharmacokinetics of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of retrovirus (i.e. human immunodeficiency virus) replication was determined in mice. Upon iv bolus administration of PMEA at 25, 100, or 500 mg/kg, PMEA was rapidly cleared from the plasma in a monoexponential and dose-independent manner (half-life, 7-12.5 min; distribution volume, 0.30-0.36 liter/kg; total body clearance, 1.21-2.41 liters/hr/kg). Irrespective of the initial PMEA dose, 67% of unchanged PMEA was recovered from the urine of mice within 24 hr after administration of PMEA. [3H]PMEA, administered as an iv bolus injection, mainly accumulated in the kidney, liver, and lungs. Significant amounts of monophosphorylated PMEA were detected in kidney and liver, but not other tissues, at 10, 30, and 60 min after iv administration of PMEA. Low but significant levels of PMEA were attained in the brain.
Insights
9-(2-phosphonylmethoxyethyl)adenine (PMEA), an antiviral, is rapidly cleared from mouse plasma. Most of the drug is excreted unchanged in urine, with accumulation in kidneys and liver.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Antiviral Drug Development
Background:
- Retroviruses, including HIV, pose significant global health challenges.
- 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent inhibitor of retroviral replication.
Purpose of the Study:
- To determine the pharmacokinetic profile of PMEA in mice.
- To understand the distribution and excretion of PMEA in vivo.
Main Methods:
- Intravenous bolus administration of PMEA (25, 100, or 500 mg/kg) or [3H]PMEA in mice.
- Plasma, urine, and tissue samples were analyzed for PMEA and its metabolites.
- Pharmacokinetic parameters were calculated, including half-life, distribution volume, and clearance.
Main Results:
- PMEA exhibited rapid, dose-independent plasma clearance with a half-life of 7-12.5 minutes.
- Approximately 67% of unchanged PMEA was recovered from urine within 24 hours.
- PMEA primarily accumulated in the kidneys, liver, and lungs, with monophosphorylated forms detected in kidneys and liver.
Conclusions:
- PMEA is rapidly eliminated from circulation in mice, predominantly via renal excretion.
- The kidney and liver are key organs for PMEA accumulation and potential metabolism.
- These findings are crucial for understanding PMEA's disposition and guiding further antiviral drug development.