Could dextroamphetamine sulfate (Metamina), in a urine chiral analysis, show both l- and d-amphetam

Fråga: Could dextroamphetamine sulfate (Metamina), in a urine chiral analysis, show both l- and d-amphetamine isomers?

The question concerns a patient who is being treated with dextroamphetamine (Metamina) orally. A urine chiral analysis has shown both isomers, d- and l-, in concentrations of 4075 ng/mL and 445 ng/mL, respectively (9.8% of the total concentration derive from l-amphetamine). Is it possible that this could be explained only by the intake of Metamina or does it rather indicate an intake of illicit amphetamine?

Sammanfattning: It is difficult to determine whether intake of additional racemic illicit amphetamine has occurred or not. Urine chiral analysis of Metamina could show both l- and d-isomers. The validity of the possible amounts of l- and d-isomers that could be found in a chiral urine analysis are difficult to assess since the documentation is insufficient.

Svar: Dextroamphetamine, also known as dextroamphetamine sulphate or d-amphetamine, is the dextrorotary isomer of amphetamine. On the other hand amphetamine, which is a chiral compound, consists of a racemic mixture that can be divided into its optical antipodes: l- and d-amphetamine with a ratio of 1:1 (1).

According to the company that supplies Metamina it should solely contain the d-isomer even though impurity of the l-isomer, maximum 0.1%, could be found (2). Through personal communication with our chief chemist at our laboratory we know that chiral analysis of Metamina in urine indicates that l-amphetamine occurs in small amounts, amply 3- 5%. The method used to perform a chiral analysis in urine at our laboratory is LC/MS (Liquid Chromatography-Mass Spectrometry). Parameters such as measurement accuracy are to be considered into the validity of the results. The measurement accuracy is about +/-10 percent (3). Information from the Medical Products Agency further indicates that both isomers occur in commercial dextroamphetamine. According to studies published in Biochemical Pharmacology (1967) about 8% of l-amphetamine could be found in commercial dextroamphetamine (4).

Another important aspect of stereo selective determination of drugs in the laboratory is that there may be significant differences in their pharmacodynamic activity and their pharmacokinetic properties. Different isomers may have different plasma concentrations due to the fact that there could be a chiral discrimination in pharmacokinetic processes. One isomer may very well be absorbed and/or metabolized and/or excreted at different rates than other isomeric forms (5). Given this fact it is not entirely clear that the ratio in the drug before administration will be the same in a chiral urine analysis. Consecutive tests would be of importance to determine the ratio in a specific patient.

One study (6) concerning quantisation of l- and d-amphetamine in hair and blood by GC/MS (Gas Chromatography-Mass Spectrometry) published 2005 included one patient treated with amphetamine racemat and three patients treated with d-amphetamine (Metamina). Even though there were only four patients combined with the fact that the samples came from hair and blood and that a different chiral analysis method was used, it still hints about the l-/d-amphetamine ratio depending on drug ingestion. Consecutive samples were taken.

Patient number one receiving amphetamine racemat had 46-48% of d-amphetamine in hair and 37-42% in blood. Because the samples were trough samples it was suggested that the lower percentage in blood could be explained by a slower metabolism of the l-amphetamine isomer, resulting in a higher concentration the longer the time after last dose.

Patient number two, receiving a daily dose of 60mg of d-amphetamine (Metamina), had approximately 88% of d-amphetamine in both hair and blood together with similar concentrations over time in three consecutive samples taken six months apart, suggested from the authors as evidence of good compliance and abstinence from illicit amphetamine. This gives a hint that amply 10% of l-amphetamine could be found in a product said to contain almost solely d-amphetamine.

Patient number three and four, also receiving only d-amphetamine, showed different percentages of d-amphetamine in hair and blood (65-88%/82-89% and 49-88%/80-86% respectively) together with varying total concentrations. This was, also according to the authors, suggesting an intake of additional racemic illicit amphetamine. The patients later confirmed this.

However, it is very important to consider the fact that documentation about occurrence of l- and d-isomers in Metamina contra analysis results is very insufficient and therefore further clarification is required. It is difficult to explain the different ratios of l- and d-isomers comparing the contents of Metamina and the analysis result in this case.

Documentation about isomeric transformation, in the body, from d- to l-amphetamine and vice versa has not been found. Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999

Metamina. Summary of product characteristics (SPC) (Recip AB)
Olof Beck, Chief Chemist, Department of Clinical Pharmacology, Karolinska University Hospital (personal communication)
Lars Gunne, Prof, Medical Products Agency (personal communication)

Rentsch KM. The importance of stereo selective determination of drugs in the clinical laboratory. J Biochem Biophys Methods 2002;54:1-9. Nyström I, Trygg T, Woxler P, Ahlner J, Kronstrand R. Quantitation of R-(-)- and S-(+)-amphetamine in hair and blood by gas chromatography-mass spectrometry: An application to compliance monitoring in adult-attention deficit hyperactivity disorder treatment. J Anal Toxicol 2005;29:682-8.