Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

V. Mahnir, B. Lin, Katalin Prokai-Tatrai, W. R. Kem

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

DMXBA (3-(2,4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg-1 iv dose, DMXBA plasma concentration declined bi-exponentially with mean (± SE) absorption and elimination half-lives of 0.71 ± 0.28 and 3.71 ± 1.12 h, respectively. The apparent steady state volume of distribution was 2150 ± 433 mL kg-1, total body clearance was 1480 ± 273 mL h-1 kg-1, and AUC(0-∞) was 3790 ± 630 ng h mL-1. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg-1, a peak plasma concentration of 1010 ± 212 ng mL-1 was observed at 10 min after dosing. Elimination half-life was 1.740 ± 0.34 h, and AUC(0-∞) was 1440 ± 358 ng h mL-1. DMXBA peak brain concentration after oral administration was 664 ± 103 ng g-1 tissue, with an essentially constant brain-plasma concentration ratio of 2.61 ± 0.34, which indicates that the drug readily passes across the blood-brain barrier. Serum protein binding was 80.3 ± 1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h-1 kg-1) was less than 2% of the total clearance (1480 ± 273 mL h-1 kg-1); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28 ± 0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism.

Original languageEnglish
Pages (from-to)147-151
Number of pages5
JournalBiopharmaceutics and Drug Disposition
Volume19
Issue number3
DOIs
StatePublished - 16 Apr 1998

Fingerprint

Cognition
Pharmacokinetics
Biological Availability
Area Under Curve
Oral Administration
Brain
3-(2,4-dimethoxybenzylidene)anabaseine
Blood-Brain Barrier
Protein Binding
Half-Life
Blood Proteins
Alzheimer Disease
High Pressure Liquid Chromatography
Pharmacology
Kidney
Liver
Pharmaceutical Preparations

Keywords

  • Alzheimer's disease
  • DMXBA
  • GTS-21
  • Nicotine
  • Nicotinic agonist
  • Pharmacokinetics

Cite this

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title = "Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition",
abstract = "DMXBA (3-(2,4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg-1 iv dose, DMXBA plasma concentration declined bi-exponentially with mean (± SE) absorption and elimination half-lives of 0.71 ± 0.28 and 3.71 ± 1.12 h, respectively. The apparent steady state volume of distribution was 2150 ± 433 mL kg-1, total body clearance was 1480 ± 273 mL h-1 kg-1, and AUC(0-∞) was 3790 ± 630 ng h mL-1. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg-1, a peak plasma concentration of 1010 ± 212 ng mL-1 was observed at 10 min after dosing. Elimination half-life was 1.740 ± 0.34 h, and AUC(0-∞) was 1440 ± 358 ng h mL-1. DMXBA peak brain concentration after oral administration was 664 ± 103 ng g-1 tissue, with an essentially constant brain-plasma concentration ratio of 2.61 ± 0.34, which indicates that the drug readily passes across the blood-brain barrier. Serum protein binding was 80.3 ± 1.1{\%}. Apparent oral bioavailability was 19{\%}. Renal clearance (21.8 mL h-1 kg-1) was less than 2{\%} of the total clearance (1480 ± 273 mL h-1 kg-1); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28 ± 0.03{\%} of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism.",
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Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition. / Mahnir, V.; Lin, B.; Prokai-Tatrai, Katalin; Kem, W. R.

In: Biopharmaceutics and Drug Disposition, Vol. 19, No. 3, 16.04.1998, p. 147-151.

Research output: Contribution to journalArticle

TY - JOUR

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