Handbook of Drug Interactions

40 Moody
1A2 and 3A4. Ranitidine and ebrotidine had some, but relatively fewer inhibitory
effects on these P450s.
Klotz et al. (155) compared the spectral dissociation constants of the H 2-receptor
antagonists with HLMs and determined the following K s values: oxmetidine, 0.2 mM;
cimetidine, 0.87 mM; ranitidine, 5.1 mM; famotidine and nizatidine, no effect up to 4
mM. In another in vitro comparison of the effect of cimetidine and nizatidine on the
1'-hydroxylation of midazolam in HLMs, Wrighton and Ring (36) determined K is of
268 and 2860 µM, respectively. For comparative purposes, the K is of ketoconazole
and nifedipine, known 3A4 inhibitors, were 0.11 and 22 µM. With the exception of
oxmetidine, for which only a single clinical study was performed, these in vitro findings
will favorably describe the interactions seen between the H 2-receptor antagonists and
benzodiazepines that rely upon P450-mediated metabolism for their elimination.
Coadministration of multiple doses of cimetidine has been found to diminish the
elimination of a number of benzodiazepines (Table 20), that include: adinazolam (156),
alprazolam (157,158), bromazepam (159), chlordiazepoxide (160), clobazam (161),
clorazepate (162), diazepam (149,163–168), flurazepam (169), midazolam (140,170),
nitrazepam (171), nordiazepam (172), and triazolam (157,158,173). Single doses of
cimetidine seem to have milder effect, but have been found to diminsih the elimination
of diazepam (174) and midazolam (154,175,176) in a dose-dependent fashion (Table
20). In all studies, but one, that monitored pharmacodynamic effects these were mildly
diminished also (Table 20). Gough et al. (165) found inhibition of diazepam pharmacokinetics
without any change in the monitored pharmacodynamic measures. Lorazepam
(166,169,174,177) and oxazepam (169,172,177), which are exclusively glucuronidated,
and temazepam (140,178), which can be glucuronidated without further metabolism,
were resistant to the effects of cimetidine. The outlier in this scheme is clotiazepam,
which appears to require P450-dependent metabolism, but was unaffected by cimetidine.
It was also resistant to inhibitory effects by ethanol (123).
Multidose ranitidine inhibited the elimination of oral diazepam (179), midazolam
(140,170,180), and triazolam (181), but was inaffective against intravenous doses of
these benzodiazepines (179,181–183), intravenous lorazepam (182), and oral temazepam
(140). A single dose of ranitidine had no effect on oral adinazolam (184), oral
midazolam (154), or infused midazolam (175). Multidose famotidine (155,185,186),
oxmetidine (155), and nizatidine (155) had no effect on the pharmacokinetics of intravenous
diazepam. A single dose of ebrotidine had no effect on oral midazolam (154;
Table 20).
Vanderveen et al. (181) found that ranitidine diminished the elimination of oral,
but not intravenous triazolam. They hypothesized that the increase in pH caused by
ranitidine was responsible for the diminished elimination of oral triazolam. The basis of
their hypothesis was that at acidic pH triazolam is in equilibrium with its more poorly
absorbed benzophenone (Fig. 12). With increased pH, less benzophenone is formed
and more triazolam is absorbed (181). The prior findings of Cox et al. (173), however,
seem to dispute this hypothesis. They administered intraduodenal infusions of triazolam
in solutions at pH 2.3, where 47% was the benzophenone, and pH 6.0, with negligible
benzophenone, and found no difference in the pharmacokinetics. Ranitidine does
appear to inhibit the metabolism of some benzodiazepines. This appears to be limited
to first-pass metabolism within either the gastrointestinal tract or the liver.