Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects.
OBJECTIVE
Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers.


METHODS
Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype.


RESULTS
The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148).


CONCLUSIONS
The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.
Park
Ji-Young
JY
Department of Pharmacology, Korea University College of Medicine, Seoul, South Korea.
Kim
Kyoung-Ah
KA
Park
Pil-Whan
PW
Lee
Ock-Je
OJ
Kang
Dong-Kyun
DK
Shon
Ji-Hong
JH
Liu
Kwang-Hyun
KH
Shin
Jae-Gook
JG
D000284:Administration, Oral; D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004247:DNA / Q000032:analysis; D017931:DNA Primers; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values
D014151:Anti-Anxiety Agents; D017931:DNA Primers; D004247:DNA; D051544:Cytochrome P-450 CYP3A; D000525:Alprazolam