Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences.
BACKGROUND
Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study.


METHODS
In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo.


RESULTS
Mean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials.


CONCLUSIONS
The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
D J
DJ
Greenblatt
L L
LL
von Moltke
J S
JS
Harmatz
M
M
Counihan
J A
JA
Graf
A L
AL
Durol
P
P
Mertzanis
S X
SX
Duan
C E
CE
Wright
R I
RI
Shader
D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D017963:Azithromycin / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D004917:Erythromycin / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014229:Triazolam / Q000378:metabolism / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D006993:Hypnotics and Sedatives; D014229:Triazolam; D004917:Erythromycin; D017963:Azithromycin; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin