Clinical Pharmacokinetics of Amfetamine and Related Substances

Abstract

Consumption of amfetamine-type stimulants, including classical amfetamines and 'designer drugs', has been recognised as one of the most significant trends in drug abuse at the end of the past century and at the beginning of the current one. The first cause is the increasing consumption amongst youth of methylenedioxy- and methoxy-substituted amfetamines, of which the pharmacology in humans is currently under investigation. Secondly, the abuse of more classical amfetamines, such as amfetamine itself and metamfetamine, continues to be highly prevalent in some geographical regions. Amfetamines are powerful psychostimulants, producing increased alertness, wakefulness, insomnia, energy and self-confidence in association with decreased fatigue and appetite as well as enhanced mood, well-being and euphoria. From a clinical pharmacokinetic perspective, amfetamine-type stimulants are rather homogeneous. Their oral bioavailability is good, with a high distribution volume (4 L/kg) and low binding to plasma proteins (less than 20%). The elimination half-life is 6-12 hours. Both hepatic and renal clearance contribute to their elimination from the body. Hepatic metabolism is extensive in most cases, but a significant percentage of the drug always remains unaltered. Amfetamine and related compounds are weak bases, with a pKa around 9.9, and a relatively low molecular weight. These characteristics allow amfetamine-type stimulants to diffuse easily across cell membranes and lipid layers and to those tissues or biological substrates with a more acidic pH than blood, facilitating their detection in alternative matrices at relatively high concentrations. In most cases, the concentrations found are higher than expected from the Henderson-Hasselbach equation. Drug monitoring in non-conventional biological matrices (e.g. saliva, hair, nails, sweat) has recently gained much attention because of its possible applications in clinical and forensic toxicology. An individual's past history of medication, compliance or drug abuse can be obtained from testing of hair and nails, whereas data on current status of drug use can be provided by analysis of sweat and saliva. Because of the physicochemical properties of amfetamine-type stimulants, this group of drugs is one of the most suitable for drug testing in non-conventional matrices.

Methylphenidate for Treating ADHD: A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage

“…MPH concentrations were much higher in OF than in blood, probably due to active secretion similar to other amphetamine-like compounds [45, 46]. Conversely, RA concentrations in OF showed an opposite trend.…”

Gas chromatography–ion trap mass spectrometry method for the simultaneous measurement of MDMA (ecstasy) and its metabolites, MDA, HMA, and HMMA in plasma and urine

“…MDMA metabolism and excretion in humans and animal models is well documented [10][11][12][13]. Over 80% of the ingested MDMA dose is eliminated after hepatic metabolism and around 20% of the dose is excreted unchanged in human urine [14]. N-demethylation of MDMA produces MDA which accounts for less than 10% of the ingested dose [15].…”

Chiral separation and quantification of R/S-amphetamine, R/S-methamphetamine, R/S-MDA, R/S-MDMA, and R/S-MDEA in whole blood by GC-EI-MS

“…The enzyme CYP2D6 is enantioselective and catalyzes the ␤-hydroxylation of AM and the demethylations in the metabolism of MDMA. This results in R/S ratios >1 in biological fluids for AM and MDMA consumed as the racemate [6][7][8].…”