Alprazolam as a probe for CYP3A using a single blood sample: pharmacokinetics of parent drug, and of alpha- and 4-hydroxy metabolites in healthy subjects.
OBJECTIVE
(1) To determine the pharmacokinetic parameters of alprazolam and its two metabolites in plasma from healthy volunteers; (2) to identify a suitable single time point to take a plasma sample for CYP3A phenotyping.


METHODS
Twelve healthy Swedish volunteers received a single oral dose of 1 mg alprazolam. Blood samples were collected before drug intake and frequently up to 72 h thereafter. A liquid-chromatography/mass-spectrometry (LC/MS) method was used for the quantification of alprazolam, and 4- and alpha-hydroxyalprazolam.


RESULTS
The interindividual variation in the area under the concentration-time curve (AUC) was two, three and fourfold for alprazolam, 4-hydroxyalprazolam and alpha-hydroxyalprazolam, respectively. Plasma concentration ratios collected between 1 h and 48 h for both alprazolam/4-hydroxyalprazolam and alprazolam/alpha-hydroxyalprazolam correlated significantly to the corresponding AUC0-infinity ratios.


CONCLUSIONS
The metabolic ratios of alprazolam to respective metabolite in a single plasma sample at 3-24 h are suggested to reflect the alprazolam 4- and alpha-hydroxylation activities. In future, it will be important to study these activities in populations where CYP3A5, in addition to CYP3A4, is expressed at a high frequency and to clarify the relative importance of the two enzymatic pathways for in vivo clearance of alprazolam.
Wennerholm
Agneta
A
Division of Clinical Pharmacology C1:68, Karolinska University Hospital, Huddinge, 141 86, Stockholm, Sweden.
Allqvist
Annika
A
Svensson
Jan-Olof
JO
Gustafsson
Lars L
LL
Mirghani
Rajaa A
RA
Bertilsson
Leif
L
D000328:Adult; D000525:Alprazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
D014151:Anti-Anxiety Agents; C032318:alpha-hydroxyalprazolam; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C503150:4-hydroxyalprazolam; D000525:Alprazolam