Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism

Abstract

1. The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.

2. In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.

3. The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.

4. The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.

5. The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.

6. Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

Keywords:

• ADHD
• cytochrome P450 (CYP450)
• uridine 5′-diphospho-glucuronosyltransferase (UGT)
• pharmacokinetics
• hepatocytes
• human liver microsomes (HLMs)
• chemical inhibition
• in vitro

Disclosure statement

RL, DL, DH, RD and HJ were employed by Myriad Neuroscience at the time of this study and received salary and stock options. MPD received research support from Alkermes, Allergen, Assurex (now Myriad Neuroscience), Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovion, Supernus, MINH, and PCORI, and has served as a consultant for Alkermes, Allergen, Assurex (Myriad Neuroscience), CMEology, Johnson and Johnson, Medscape, Myriad Genetics, Neuronetics, Sage, and Sunovion. JAF has received research support from Healix Pharmaceuticals and Tetra Discovery Partners, Inc. EN has received research funding for a clinical trial with Emalex Pharmaceuticals and has served as a member of the scientific advisory board for Myriad Genetics. ESC, SW, and JL were employed by Myriad Genetics at the time of this study and received salary and stock options.