CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4beta-hydroxycholesterol levels.
OBJECTIVE
A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A.


RESULTS
In patients treated with efavirenz, the median plasma 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-hydroxycholesterol of -9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4beta-hydroxycholesterol levels (p < 0.0001).


CONCLUSIONS
Changes in plasma 4beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.
Josephson
F
F
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. filip.josephson@karolinska.se
Bertilsson
L
L
Böttiger
Y
Y
Flamholc
L
L
Gisslén
M
M
Ormaasen
V
V
Sönnerborg
A
A
Diczfalusy
U
U
D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000378:metabolism; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D006888:Hydroxycholesterols; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; C099828:cholest-5-ene-3,4-diol; D061466:Lopinavir; D000069446:Atazanavir Sulfate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C098320:efavirenz; D019438:Ritonavir