A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.
The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
J B
JB
Dumond
M
M
Vourvahis
N L
NL
Rezk
K B
KB
Patterson
H-C
HC
Tien
N
N
White
S H
SH
Jennings
S O
SO
Choi
J
J
Li
M J
MJ
Wagner
N M
NM
La-Beck
M
M
Drulak
J P
JP
Sabo
M A
MA
Castles
T R
TR
Macgregor
A D M
AD
Kashuba
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D004364:Pharmaceutical Preparations; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; D019438:Ritonavir; C107201:tipranavir