Blood—Brain Barrier Transport of Butanol and Water Relative to N-Isopropyl-p-Iodoamphetamine as the Internal Reference

Abstract

The literature regarding the blood--brain barrier (BBB) transport of butanol is conflicting as studies report both incomplete and complete extraction of butanol by the brain. In this work the BBB transport of both [14C]butanol and [3H]water was studied using the carotid injection technique in conscious and in ketamine- or pentobarbital-anesthetized rats employing N-isopropyl-p-[125I]iodoamphetamine ([125I]IMP) as the internal reference and as a fluid microsphere. The three isotopes (3H, 125I, 14C) were conveniently counted simultaneously in a liquid scintillation spectrometer. IMP is essentially completely sequestered by the brain for at least 1 min in conscious rats and for 2 min in anesthetized animals. Butanol extraction by rat forebrain is not flow limited but ranges between 77 +/- 1 and 87 +/- 1% for the three conditions. The incomplete extraction of butanol by the forebrain is due to diffusion restriction of butanol clearance in some regions (frontal cortex, colliculi) but not in others (caudate, hippocampus, olfactory bulb). The permeability-surface area product/cerebral blood flow ratio of butanol and water in rat forebrain remains relatively constant, 1.7 +/- 0.2 and 1.0 +/- 0.1, respectively, despite a twofold increase in cerebral blood flow in conscious relative to pentobarbital-anesthetized rats. The absence of an inverse relationship between flow and butanol or water extraction is consistent with capillary recruitment being the principal mechanism underlying changes in cerebral blood flow in anesthesia. The diffusion restriction of BBB transport of butanol in some regions, but not in others, necessitates a careful regional analysis of BBB permeability to butanol prior to usage of this compound as a cerebral blood flow marker.

A Double-Radionuclide Autoradiographic Method Using N-Isopropyl-Iodoamphetamine for Sequential Measurements of Local Cerebral Blood Flow

“…These results confirm previous reports that IMP has a first-pass extraction close to 100%, with a minimal brain-to-blood back diffusion (Winchell et aI., 1980b;Kuhl et aI., 1982;Pardridge and Fierer, 1985), probably because of its affinity for high-ca pacity and relatively nonspecific binding sites (Winchell et aI., 1980a). Therefore, IMP does be have as a "chemical microsphere," and it can be used for sequential autoradiographic determina tions of LCBF.…”

“…Several previous studies have shown that the ex traction of IMP approaches the flow-limited value under physiological conditions (Winchell et aI., 1980b;Kuhl et aI., 1982;Pardridge and Fierer, 1985), but Kuhl et ai. (1982) found that brain ex traction of IMP was decreased from a value of 92 to 74% when the arterial blood pH was lowered from 7.35 to 7.10.…”

“…(1982) found that brain ex traction of IMP was decreased from a value of 92 to 74% when the arterial blood pH was lowered from 7.35 to 7.10. Pardridge's group proposed that this may be a pH effect (Pardridge and Fierer, 1985) since amphetamine(s) as well as other lipophilic basic amines are transported through the blood brain barrier substantially more slowly at lower pH (Pardridge and Connor, 1973;Pardridge et al, 1984). Therefore, it appears that LCBF measure ments with IMP as tracer should be further vali dated under conditions associating high CBF with low arterial blood pH, e.g., during respiratory aci dosis.…”

“…One such agent is N-isopropyl-p-iodoam phetamine (IMP), which is also of proven value in experimental autoradiographic determinations of LCBF (Kuhl et aI., 1982;Lear et aI., 1982;Rapin et aI., 1984). IMP has been shown to act in the brain as a "chemical microsphere": (a) It has a first-pass extraction coefficient of almost 1 00% (Winchell et aI., 1980b;Kuhl et aI., 1982;Pardridge and Fierer, 1985); (b) Kuhl et al (1982) found that there is no significant release from the brain nor redistribution within brain tissue for at least 5 min following intra carotid injection; (c) results from several groups further suggest that IMP distribution represents CBF pattern during the first 30 min after tracer in jection (Kuhl et aI., 1982;Rapin et aI., 1983a-c) in the cortex, thalamus, and brainstem although not in the cerebellum (Jones et aI., 1986). Considering these properties, sequential quantitative autoradio-graphic LCBF determinations should be possible, at least in some major brain structures, using suc cessive intravascular injections of IMP labelled with different radionuclides.…”

Encefalopatía tóxica por isopropanol: Sobre-exposición accidental a gas propano

“…El isopropanol y el butanol son alguno de los metabolitos identificados, alcoholes que tienen especial afinidad por el hipocampo y el bulbo olfatorio 9 .…”