The use of toxicokinetics for the safety assessment of drugs acting in the brain.
Pharmacological and toxicological studies undertaken on drugs that affect the brain are frequently performed in disparate species under various experimental conditions, at doses often greatly in excess of those expected to be administered to humans, and the findings are extrapolated implicitly or explicitly with scant regard to differences in the biodisposition of the drugs. Such considerations are necessary since: 1. Species; 2. Strain; 3. Gender; 4. Route; 5. Dose; 6. Frequency and time of administration; 7. Temperature; 8. Coadministration of drugs; and 9. Surgical manipulation are but some of the factors that have been shown to influence the kinetics and metabolism of drugs. This article, using MDMA and other phenylethylamines as examples, provides evidence for the need to measure the exposure of the drugs and their active metabolites in blood and brain (toxicokinetics) in order that conclusions based only on dynamic, biochemical, or histological evidence are more pertinent. Further, the combined use of toxicokinetic-dynamic modeling can lead to a better appreciation of the mechanisms involved and a more useful approach to the calculation of safety margins.
Campbell
D B
DB
Servier Research and Development, Fulmer, Slough, UK.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D004341:Drug Evaluation / Q000379:methods*; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics* / Q000633:toxicity*; D009498:Neurotoxins / Q000493:pharmacokinetics / Q000633:toxicity; D010627:Phenethylamines / Q000493:pharmacokinetics* / Q000633:toxicity*; D012727:Sex Characteristics; D013045:Species Specificity
D001798:Blood Proteins; D009498:Neurotoxins; D010627:Phenethylamines; D018817:N-Methyl-3,4-methylenedioxyamphetamine