Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?
BACKGROUND
In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited.


METHODS
We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients.


RESULTS
Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644).


CONCLUSIONS
The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients.
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland. alexander.jetter@usz.ch
Alexander
A
Jetter
Gerd
G
Fätkenheuer
Dorothee
D
Frank
Tobias
T
Klaassen
Angela
A
Seeringer
Oxana
O
Doroshyenko
Julia
J
Kirchheiner
Wolfgang
W
Hein
Edgar
E
Schömig
Uwe
U
Fuhr
Christoph
C
Wyen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics; D015536:Down-Regulation; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D061466:Lopinavir; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D011744:Pyrimidinones / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D003915:Dextromethorphan; D004077:Digoxin; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; D008874:Midazolam