Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated enzyme induction.
OBJECTIVE
To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects.


METHODS
Eight older subjects (67.1 +/- 1.2 years mean +/- s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady-state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV-conduction were measured by the maximum PR interval prolongation (%).


RESULTS
Bioavailability of the cardiovascularly more active S-verapamil decreased from 14.2 +/- 4.3% on day 4 to 0.6 +/- 0.5% on day 16 (P < 0.001). As a consequence, effects of orally administered verapamil on the AV-conduction were nearly abolished (14.4 +/- 9.4% vs 2.7 +/- 2.6%, P < 0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7 +/- 22.1% vs 91.6 +/- 6.6%, P < 0.01) and to a minor extent to induction of hepatic metabolism (73.7 +/- 9.4% vs 91.6 +/- 5.3%, P < 0.01).


CONCLUSIONS
Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.
Fromm
M F
MF
Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Dilger
K
K
Busse
D
D
Kroemer
H K
HK
Eichelbaum
M
M
Klotz
U
U
D000368:Aged; D000375:Aging / Q000378:metabolism*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D012016:Reference Values; D014700:Verapamil / Q000493:pharmacokinetics* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D014700:Verapamil