Effects of combination of vasodilator drugs and hypertonic solutions on methotrexate distribution into the rat brain

Jpn J Pharmacol. 1988 Nov;48(3):373-6. doi: 10.1254/jjp.48.373.

Abstract

The present experiments were designed to find a method to facilitate methotrexate (MTX) transfer into rat brain tissue. Adult male Wistar-Kyoto strain rats, anesthetized with pentobarbital-Na, received an infusion of the drug solution to be tested into the right internal carotid artery (5 ml/min, 30 sec) 5 min before injection of MTX (7 mg/kg). After 10 min, the MTX levels in the cerebral hemispheres were estimated as a peak height ratio unit of MTX vs. the internal standard by high performance liquid chromatography. MTX was undetectable in either hemisphere after the pretreatment with saline alone or 15% mannitol-saline. The MTX levels in the right hemisphere were about 10 after the pretreatment with 20% mannitol-saline, while MTX was undetectable in the left hemisphere. In contrast, the MTX levels in the right hemisphere were dose-dependently increased to about 25, 130 and 60, 100, respectively, when nitroglycerin (NTG, 2.5 or 7.5 micrograms/rat) or nicardipine-HCl (NIC, 1.25 or 2.5 micrograms/rat) was administered together with 20% mannitol-saline. These vasodilator drugs, however, had no effect when tested in combination with saline or 15% mannitol-saline. It is assumed that an increase in cerebrovascular blood flow induced by NTG or NIC enhances the MTX transfer into the brain once the blood brain barrier is opened by hypertonic solutions.

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Cerebrovascular Circulation / drug effects
  • Hypertonic Solutions / administration & dosage
  • Male
  • Mannitol / administration & dosage
  • Methotrexate / pharmacokinetics*
  • Nicardipine / pharmacology
  • Nitroglycerin / pharmacology
  • Osmotic Pressure
  • Rats
  • Rats, Inbred WKY
  • Vasodilator Agents / administration & dosage
  • Vasodilator Agents / pharmacology*

Substances

  • Hypertonic Solutions
  • Vasodilator Agents
  • Mannitol
  • Nicardipine
  • Nitroglycerin
  • Methotrexate