Variability in drug metabolizing enzyme activity in HIV-infected patients.
OBJECTIVE
To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.


METHODS
Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.


RESULTS
Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFalpha concentrations correlated with lower CYP2D6 and CYP3A4 activity.


CONCLUSIONS
Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.
Jones
Amanda E
AE
School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. amanda_jones@unc.edu
Brown
Kevin C
KC
Werner
Rebecca E
RE
Gotzkowsky
Karl
K
Gaedigk
Andrea
A
Blake
Mike
M
Hein
David W
DW
van der Horst
Charles
C
Kashuba
Angela D M
AD
D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002110:Caffeine / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014969:Xanthine Oxidase / Q000378:metabolism*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002110:Caffeine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D008874:Midazolam