Influence of polymorphic N-acetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid.
OBJECTIVE
To determine in patients receiving isoniazid prophylaxis whether an increase in the CYP2E1 dependent formation clearance of acetaminophen (paracetamol) to N-acetyl-p-benzoquinone imine (NAPQI) occurs during a normal 24-hour isoniazid dose interval and whether the interaction is dependent on acetylation status.


METHODS
Acetaminophen elimination kinetics were determined on four different occasions. Ten subjects were assigned to receive acetaminophen either simultaneously with the 8 am dose of isoniazid or 12 hours after the isoniazid dose. One week later, on the last day of isoniazid therapy, subjects received acetaminophen at the alternate time of day. The control phase acetaminophen administrations were repeated 1 and 2 weeks later, following the initial randomization. Isoniazid acetylation (NAT2) genotype was determined by analysis of genomic DNA obtained from peripheral blood leukocytes.


RESULTS
The mean NAPQI formation clearance was inhibited 57% when acetaminophen and isoniazid were coadministered but was unchanged compared with time-matched control when acetaminophen was given 12 hours after the isoniazid dose. However, when data from subjects was segregated according to isoniazid (INH) acetylation phenotype, the mean ratio of NAPQI formation clearances (+INH/-INH) with 8 PM acetaminophen was significantly higher for fast acetylators compared with slow acetylators (1.36 versus 0.68; p = 0.006).


CONCLUSIONS
Fast metabolizers of isoniazid appeared to clear the inducer or inhibitor from the active site of CYP2E1 more rapidly, which resulted in an increased formation of NAPQI 12 hours after the isoniazid dose. In contrast, formation of NAPQI for slow isoniazid metabolizers remained inhibited.
Chien
J Y
JY
Department of Pharmaceutics, University of Washington, Seattle 98195-7610, USA.
Peter
R M
RM
Nolan
C M
CM
Wartell
C
C
Slattery
J T
JT
Nelson
S D
SD
Carithers
R L
RL
Thummel
K E
KE
D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000107:Acetylation; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects*; D004334:Drug Administration Schedule; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic
D018712:Analgesics, Non-Narcotic; D000995:Antitubercular Agents; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; D007538:Isoniazid