TY - JOUR
T1 - Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam
AU - Abernethy, Darrell R.
AU - Greenblatt, David J.
AU - Divoll, Divoll
AU - Moschitto, Lawrence J.
AU - Harmatz, Jerold S.
AU - Shader, Richard I.
PY - 1983/6
Y1 - 1983/6
N2 - The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P<0.005), resulting in significantly prolonged elimination half-life (16.6 versus 12.4h, P<0.005). For triazolam, which has higher hepatic clearance and an intermediate extraction ratio, total clearance was reduced by cimetidine (3.9 versus 5.9 ml/min/kg), causing a significant increase in total area under the plasma concentration curve (25 versus 38 ng/ml x h, P<0.02). However, elimination half-life of triazolam was not influenced by cimetidine (3.3 versus 3.2 h), indicating that the reduction in clearance was manifested as increased systemic availability. Thus, cimetidine impairs the clearance of both alprazolam and triazolam, but the consequences of the kinetic change are different because of the differing hepatic extraction profiles of the two drugs.
AB - The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P<0.005), resulting in significantly prolonged elimination half-life (16.6 versus 12.4h, P<0.005). For triazolam, which has higher hepatic clearance and an intermediate extraction ratio, total clearance was reduced by cimetidine (3.9 versus 5.9 ml/min/kg), causing a significant increase in total area under the plasma concentration curve (25 versus 38 ng/ml x h, P<0.02). However, elimination half-life of triazolam was not influenced by cimetidine (3.3 versus 3.2 h), indicating that the reduction in clearance was manifested as increased systemic availability. Thus, cimetidine impairs the clearance of both alprazolam and triazolam, but the consequences of the kinetic change are different because of the differing hepatic extraction profiles of the two drugs.
KW - Alprazolam
KW - Cimetidine
KW - Triazolam
KW - Triazolobenzodiazepine
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U2 - 10.1007/BF00436169
DO - 10.1007/BF00436169
M3 - Article
C2 - 6137021
AN - SCOPUS:0020580164
SN - 0033-3158
VL - 80
SP - 275
EP - 278
JO - Psychopharmacology
JF - Psychopharmacology
IS - 3
ER -