AimsThe aims of this study were to examine the in vitro enzyme kinetics and CYP isoform selectivity of perhexiline monohydroxylation using human liver microsomes. Methods Conversion of rac-perhexiline to monohydroxyperhexiline by human liver microsomes was assessed using a high-performance liquid chromatography assay with precolumn derivatization to measure the formation rate of the product. Isoform selective inhibitors were used to define the CYP isoform profile of perhexiline monohydroxylation. Results The rate of perhexiline monohydroxylation with microsomes from 20 livers varied 50-fold. The activity in 18 phenotypic perhexiline extensive metabolizer (PEM) livers varied about five-fold. The apparent K m was 3.3 ± 1.5 µ M , the V max was 9.1 ± 3.1 pmol min − 1 mg − 1 microsomal protein and the in vitro intrinsic clearance (V max /K m ) was 2.9 ± 0.5 m l min − 1 mg − 1 microsomal protein in the extensive metabolizer livers. The corresponding values in the poor metabolizer livers were: apparent K m 124 ± 141 µ M ; V max 1.4 ± 0.6 pmol min − 1 mg − 1 microsomal protein; and intrinsic clearance 0.026 µ l min − 1 mg − 1 microsomal protein. Quinidine almost completely inhibited perhexiline monohydroxylation activity, but inhibitors selective for other CYP isoforms had little effect. Conclusions Perhexiline monohydroxylation is almost exclusively catalysed by CYP2D6 with activities being about 100-fold lower in CYP2D6 poor metabolizers than in extensive metabolizers. The in vitro data predict the in vivo saturable metabolism and pharmacogenetics of perhexiline.
The effects of lidocaine in high doses, i.e. higher than seizure doses, on cerebral function and metabolism are reviewed. Evidence is presented that lidocaine (160 mg/kg) reduces membrane Na+-K+ permeability, restricts leak fluxes of these ions, and decreases the load on the associated ion transport. In the ischemic brain (circulatory arrest in dogs on cardiopulmonary bypass circulation), lidocaine delays K+ efflux, indicating reduced membrane permeability. In the nonischemic brain lidocaine has two effects. One is to abolish electrocortical activity and reduce oxygen and glucose consumption accordingly (‘barbiturate-like’ effect). The other is a specific membrane sealing effect by which Na+-K+ leak fluxes are restricted and associated demand for active transport accordingly reduced. By this effect lidocaine is able to reduce cerebral metabolism by an additional 15–20% below the barbiturate minimum at flat EEC These effects of lidocaine resemble those of hypothermia and may enhance the hypothermic protection of the ischemic brain.
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