Ritonavir greatly impairs CYP3A activity in HIV infection with chronic viral hepatitis.
OBJECTIVE
Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. We examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity.


METHODS
Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity.


RESULTS
CYP3A activity was expressed as oral clearance of the midazolam probe. In HIV-positive subjects not on ritonavir, CYP3A activity (mean +/- SD) did not differ between subjects by CVH (no CVH, controls: 28.5 +/- 9.0 vs. CVH+: 23.2 +/- 6.2 mL/min/kg, not significant). In those on ritonavir (R), CYP3A activity was 7% of controls (R: 2.1 +/- 0.8 vs. no R 28.5 +/- 9.0 mL/min/kg, P < 0.0004). CYP3A activity in subjects on ritonavir and with CVH was further reduced to 4% of controls (no CVH, R+ 2.1 +/- 0.8 vs. R+, CVH+ 1.0 +/- 0.4 mL/min/kg, P < 0.006).


CONCLUSIONS
Ritonavir markedly decreases CYP3A activity. In the presence of CVH, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with CVH impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir.
Knox
Tamsin A
TA
Nutrition/Infection Division, Department of Public Health and Family Medicine, Tufts University School of Medicine, Boston, MA 02111, USA. tamsin.knox@tufts.edu
Oleson
Lauren
L
von Moltke
Lisa L
LL
Kaufman
Rhonda C
RC
Wanke
Christine A
CA
Greenblatt
David J
DJ
D000284:Administration, Oral; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D019438:Ritonavir / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use
D065607:Cytochrome P-450 Enzyme Inhibitors; D018757:GABA Modulators; D017320:HIV Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam