Jc. Gorski et al., THE CONTRIBUTION OF INTESTINAL AND HEPATIC CYP3A TO THE INTERACTION BETWEEN MIDAZOLAM AND CLARITHROMYCIN, Clinical pharmacology and therapeutics, 64(2), 1998, pp. 133-143
Objective: To assess the relative contribution of intestinal and hepat
ic CYP3A inhibition to the interaction between the prototypic CYP3A su
bstrates midazolam and clarithromycin, Methods:: On day 1, 16 voluntee
rs (eight men and eight women; age range, 20 to 40 years; weight range
, 45 to 100 kg) received simultaneous doses of midazolam intravenously
(0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, N-
15(3)-midazolam), Starting on day 2, 500 mg clarithromycin was adminis
tered orally twice daily for 7 days, On day 8, intravenous and oral do
ses of midazolam were administered 2 hours after the final clarithromy
cin dose. Blood and urine samples were assayed for midazolam, N-15(3)-
midazolam, and metabolites by gas chromatography-mass spectrometry, Re
sults: There was no significant (p > 0.05) difference in the urinary e
xcretion of 1'-hydroxymidazolam after intravenous and oral dosing on d
ay 1 or day 8, indicating that the oral dose was completely absorbed i
nto the gut wall. The oral clearance of midazolam was found to be sign
ificantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L
/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.
35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg), For women not receiving oral
contraceptives (n = 6) a significant gender-related difference was obs
erved for systemic and oral clearance and for area under the curve and
elimination half-life after oral administration. A significant (p < 0
.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/
hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral
midazolam availability was significantly increased from 0.31 +/- 0.1
to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and
oral availability were significantly increased from 0.42 +/- 0.2 to 0.
83 +/-: 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A si
gnificant correlation was observed between intestinal and oral availab
ility (n = 32, r = 0.98, p < 0.05), After clarithromycin administratio
n, a significant correlation was observed between the initial hepatic
or intestinal availability and the relative increase in hepatic or int
estinal availability, respectively. Female subjects exhibited a greate
r extent of interaction after oral and intravenous dosing than male su
bjects (p < 0.05),Conclusion: These data indicate that in addition to
the liver, the intestine is a major site of the interaction between or
al midazolam and clarithromycin. Interindividual variability in first-
pass extraction of high-affinity CYP3A substrates such as midazolam is
primarily a function of intestinal enzyme activity.