GUT WALL METABOLISM OF VERAPAMIL IN OLDER-PEOPLE - EFFECTS OF RIFAMPICIN-MEDIATED ENZYME-INDUCTION

Aims To investigate prehepatic metabolism of verapamil and its inducib ility by rifampicin in older subjects. Methods Eight older subjects (6 7.1 +/- 1.2 years mean +/- s.d.) received racemic, unlabelled verapami l orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) w as 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) b ioavailability, prehepatic and hepatic extraction of verapamil were de termined. The effects of verapamil on AV-conduction were measured by t he maximum PR interval prolongation (%). Results Bioavailability of th e 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, ef fects of orally administered verapamil on the AV-conduction were nearl y abolished (14.4 +/- 9.4% vs 2.7 +/- 2.6%, P < 0.01). This could be a ttributed to a considerable increase of prehepatic extraction during t reatment with rifampicin (41.7 +/- 22.1% vs 91.6 +/- 6.6%, P < 0.01) a nd 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 ver apamil occurred in the group of older people investigated. Induction o f gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with nfampicin in this group of old er subjects.