Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers.
OBJECTIVE
The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF).


METHODS
: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers.


METHODS
Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4-17. CYP2C9 and CYP2C19 activities were quantified by S-WARF AUC0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively.


RESULTS
After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively.


CONCLUSIONS
LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.
Yeh
Rosa F
RF
School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
Gaver
Vincent E
VE
Patterson
Kristine B
KB
Rezk
Naser L
NL
Baxter-Meheux
Faustina
F
Blake
Michael J
MJ
Eron
Joseph J
JJ
Klein
Cheri E
CE
Rublein
John C
JC
Kashuba
Angela D M
AD
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D015415:Biomarkers / Q000652:urine; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D018023:HIV Seronegativity; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D061466:Lopinavir; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage*; D019438:Ritonavir / Q000008:administration & dosage*; D013379:Substrate Specificity; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
D015415:Biomarkers; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D002110:Caffeine; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D019438:Ritonavir; D008874:Midazolam