How does inhibiting the metabolism of a drug go on to potentiate it?

[CYP2D6]

Glutethimide is an inducer of CYP2D6 and as a result extremely potentiates codeine. However I have heard many times that in order to potentiate something you have to inhibit the enzymes that metabolise it. For instance:

"Cimetidine is also known to potentiate the effects of several opioids, including tramadol, which are partially metabolized via the cytochrome P450 pathway, via inhibiting their metabolism and a temporary decrease of liver function due to reduced hepatic blood flow. This can lead to extreme plasma levels of these drugs and can easily lead to a fatal overdose." (from wikipedia)

Does this mean it inhibits the enzymes that result in inactive metabolites thus freeing up more to be converted to active metabolites. Or does it mean that by inhibiting, it takes longer for something to be metabolised thus somehow builds up much more than normal? And is codeine different to most other drugs in that not only is it a pro-drug but it is only absorbed via first-pass metabolism or is that quite common amongst drugs?

Which is it? Inducing/Inhibiting?

Can anyone give some hard pharmacological evidence to finally put the nail in the coffin about potentiation? I'm so fucking sick of reading so much conflicting evidence.

 

[neurotic]

yeah like rivers said it

codeine and tramadol are pro-drugs, inactive (or barely active) on their own, they need CYP2D6 to be converted to morphine and O-desmethyltramadol, respectively. so induction of this enzyme potentiate these two drugs

 

[CYP2D6]

Okay cool, so with pro drugs you want to induce the enzymes that convert them right? Why does Tagamet potentiation codeine then? Also, with regards to other drugs such as Oxy, why does inhibiting their metabolism potentiation them? Intuitively, I would think you would want to induce their metabolism but why is the opposite true?

 

[neurotic]

IM NOT SURE though i believe oxy is metabolized by CYP3A4 - metabolized into oxymorph and some other uneffective stuff -, so inhibiting this enzyme, will prevent oxy from being metabolised, and you'll have oxy for more time in your system.

cimetidine is an anti-histamine (like benadryl). besides relieving the itch codeine causes, it also makes you drowsy (so they say) so that would add to the sedating effects of the high, supposedly. nothing to do with enzymes. i've never tried that combo because codeine works zero for me (tried up to 360mg no tolerance), because i lack the CYP2D6 enzyme (hence nothing or nearly nothing is methabolized into morphine). this is true for tramadol too. i don't get high at all even at almost 400mgs not tolerance