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I am searching for data showing whether (or not) the induction potential , in particular of PgP, by carbamazepine is dose-dependent.
Secondly, apparently inconsistent results were published on the location of PgP induction for PgP substrates (rifampicin induces only gut wall PgP, not in kidney for talinolol? No induction of renal digoxin clearance versus induction of PgP for paliperidone being mainly renal). Could differences in ionization constants between substrates (and pH-dependent affinity for PgP) explain why the bioavailability of some substrates is preferentially affected by induction of renal PgP whereas for other substrates the induction of gut wall PgP seems to be of primary importance. Or any other thoughts?
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Carbamazepine induction of PGP and/or CYP3A is modulated by PXR. A
useful reference may be: Br J Clin Pharmacol 62 :2 237-242 237. Ofcourse
it is dose dependent, since when no dose is given there is no induction.
The question whether it is dose dependent in the clinical relevant
dosing range. This, ofcourse, depends on the localisation of the cells
I wouldn't be surprised if induction depends on tissue AND cellular
penetration of the inducer, since PXR is a nuclear receptor. Absence of
an inductor would result in absence of induction. This also often
observed with e.g. CYP3A4 inhibitors: grapefruitjuice does not pass the
gut wall and only inhibits CYP3A4 in the intestines. Other CYP3A
inhibitors like ritonavir enter the systemic circulation and are capable
of inhibiting hepatic CYP3A as well. Carbamazepine enters the systemic
Rob ter Heine
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