Role of chiral chromatography in therapeutic drug monitoring and in clinical and forensic toxicology.
Advances in chiral chromatographic separations have given pharmacologists and toxicologists the tools to examine unexpected clinical results involving chiral drugs. The ability to unravel complex phenomena associated with drug transport and drug metabolism is presented in this manuscript. The relation between the chirality of the drug mefloquine and the intracellular concentrations of the drug cyclosporine is illustrated by examining the effect of the enantiomers of mefloquine on the transport activity of P-glycoprotein (Pgp). These studies were conducted using a liquid chromatographic column containing immobilized Pgp. The results demonstrated that (+)-mefloquine competitively displaced the Pgp substrate cyclosporine whereas (-)-mefloquine had no effect on cyclosporine-Pgp binding. The data suggest that cyclosporine cellular and CNS concentrations can be increased through the concomitant administration of (+)-mefloquine. The use of chirality in clinical and forensic situations is also illustrated by the metabolism of the enantiomers of ketamine (KET). The plasma concentrations of (+)-KET and (-)-KET and the norketamine metabolites (+)-NK and (-)-NK were measured in rat plasma using enantioselective gas chromatography. The separations were accomplished using a gas chromatography chiral stationary phase based on beta-cyclodextrin. The pharmacokinetic profiles of (+)-, (-)-KET and (+)-, (-)-NK were determined in control and protein-calorie malnourished (PCM) rats to determine the effect of PCM on ketamine metabolism and clearance. The results indicate that PCM produced a significant and stereoselective decrease in KET and NK metabolism. The data suggest that the effects of environmental factors (smoking, alcohol use, diet) and drug interactions (coadministered agents) can be measured using the changes in stereochemical metabolic and pharmacokinetic patterns of KET and similar drugs.
Williams
Marion L
ML
Department of Oncology, Leicester University, Leicester, United Kingdom.
Wainer
Irving W
IW
D002849:Chromatography, Gas / Q000379:methods*; D016572:Cyclosporine / Q000032:analysis / Q000737:chemistry; D016903:Drug Monitoring / Q000379:methods*; D005554:Forensic Medicine / Q000379:methods*; D006801:Humans; D007536:Isomerism; D007649:Ketamine / Q000032:analysis / Q000737:chemistry; D015767:Mefloquine / Q000032:analysis / Q000737:chemistry; D014116:Toxicology / Q000379:methods*
D007649:Ketamine; D016572:Cyclosporine; D015767:Mefloquine