See, now this is the problem with trying to make complex scientific points relatively simple. They never are. Biology and physiology are complicated and thus we end up minimizing or overlooking important aspects at times. Luckily in the blogosphere someone is usually all over it.
Abel Pharmboy responded to my recent post on a paper comparing MDMA pharmacokinetics between humans and one of the animal models which has generated the most specific and controversial data as a real pharmacologist should:
Getting back to other differences even within a given species is that the initial, non-conjugative metabolism of MDMA is mediated by CYP2D6, a notoriously polymorphic enzyme. In humans, there are significant interethnic differences in 2D6 activity: ~75 allelic variations that are grouped into four phenotypes: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). (nice free full-text review, albeit in the oncology setting, by CYP clinical pharm guru David Flockhart and colleagues.)
So, if there is toxicity in humans, it is important to consider whether the parent MDMA or any number of its metabolites are neurotoxic and whether there are correlations of toxicity with individuals any of the four phenotypes. As if that is not complicated enough, the methylenedioxy group (the MD of MDMA) is notorious for mechanism-based inhibition of P450 activities and I'm having trouble thinking of whether this would be have more or less influence on a poor or ultra-rapid metabolizing individual.
Hammer meet head of nail.
The research group headed by Rafael de la Torre has been the most prolific in determining the pharmacokinetics and metabolism of MDMA in humans. The group of Marilyn Huestis has contributed recent papers as well. One of the more readily understandable demonstrations was in the following paper from the de la Torre group.
The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans.
O'Mathúna B, Farré M, Rostami-Hodjegan A, Yang J, Cuyàs E, Torrens M, Pardo R, Abanades S, Maluf S, Tucker GT, de la Torre R. J Clin Psychopharmacol. 2008 Oct;28(5):523-9.
This study relies on the fact that about 90% of dextromethorphan is metabolized by CYP2D6 into dextrorphan, thus the DEX/DOR ratio is a good marker for any alterations in the functional capability of CYP2D6 enzyme. The most important part of the design was to compare the plasma levels of DEX and DOR following administration of DEX four hours after MDMA with those determined in the absence of MDMA. From the figure, it is clear that plasma DEX is much higher, and DOR much lower, when DEX is administered after MDMA. Thus, Abel's supposition is quite correct: MDMA inhibits the function of the enzyme that is normally responsible for metabolizing it.
There was an older paper from the group, Farré et al, 2004, which examined the effects of MDMA administered to humans twice at a 24 hr interval. The peak plasma level of MDMA was 77% higher and the AUC was 29% greater on the second administration. These data are consistent with those reported for one of the nonhuman primate repeated-dose studies in which the plasma levels in monkeys were higher after the 7th dose (1st of day 4) compared with the first.
Together these types of observations confirm the in vivo reality of so-called mechanism-based inhibition of hepatic enzynmes when it comes to MDMA. It points to another couple of sources of variability when we are trying to predict risk of a given dose of MDMA. This may be particularly important for boosting or multi-day dosing but there is also another can of worms. As noted in the O'Mathuna paper:
Cytochrome P450 isoform 2D6 accounts for only a small percentage of total hepatic cytochrome P450 (¨1%- 2%)5,6 but is esponsible for the metabolism of approximately 20% to 30% of marketed pharmaceuticals, including tamoxifen, antidepressants such as imipramine, nortriptyline, maprotiline, and the antianginal agent perhexiline.
I'll have to leave the issue of genetic differences in CYP2D6 functional activity across individuals for another time. As one brief lead, there was one paper, de la Torre et al, 2005, which looked at some of the CYP2D6 genetic variants and included one (functional) poor metabolizer. The reason I'm leaving this for another post is that de la Torre's reviews tend to conclude that the mechanism-based inhibition has a larger effect on MDMA pharmacokinetic parameters than do genetically-mediated constitutive differences in CYP2D6 capability. Sounds complex, doesn't it?