Abstract
The pharmacokinetics of alprazolam (ALP) after i.v. and p.o. administration in rats were characterized. ALP decayed biexponentially after the i.v. dose (1.25 mg/kg), but the concentration-time profiles after the p.o. doses (7 and 12.5 mg/kg) exhibited a double-peak phenomenon. The presence of two peaks was confirmed by statistical analysis of the serum concentration data of ALP, as well as by observed double peaks in the serum concentration-time profiles of the two active metabolites (α-hydroxyalprazolam and 4-hydroxyalprazolam). An absorption model incorporating a delay site is proposed to describe the data, and the absolute oral bioavailability is estimated to be about 30%. The two peaks were ∼80 to 115 min apart, and there was a delay in the absorption of close to 80% of oral ALP, regardless of dose. We hypothesize that the mechanism underlying the double-peak phenomenon is due to reduction in gastric motility caused by the muscle relaxant effect of ALP. This hypothesis is supported by the observed longer delay in the appearance of the second peak at the higher p.o. dose. Enterohepatic recycling is precluded from being the underlying mechanism, because of the presence of double peaks after the p.o. doses but not after the i.v. dose. This is the first reported case of double peaks for oral ALP, and this phenomenon has not been reported for other benzodiazepines. The double-peak phenomenon caused by the hypothesized mechanism may have important therapeutic and drug interaction implications, especially because benzodiazepines are commonly coadministered with other drugs.
Footnotes
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Send reprint requests to: Chyan E. Lau, Ph.D., Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854-8020. E-mail:clau{at}rci.rutgers.edu
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This research was supported by National Institute on Drug Abuse Grant R37 DA03117 (J.L.F.).
- Abbreviations used are::
- ALP
- alprazolam
- AIC
- Akaike’s information criterion
- AUC
- area under the curve
- BZ
- benzodiazepine
- C1max
- maximum concentration for the first peak
- C2max
- maximum concentration for the second peak
- Cmin
- minimum concentration
- Cl
- clearance
- F
- bioavailability
- f
- fraction of bioavailable ALP that enters the delay site
- N
- number of delay compartments
- PK
- pharmacokinetics
- Td
- delay time
- T1max
- time at whichC1max occurred
- T2max
- time at whichC2max occurred
- Tmin
- time at whichCmin occurred
- Vc
- volume of distribution in the central compartment
- Vss
- volume of distribution at steady state
- α-OHALP
- α-hydroxyalprazolam
- 4-OHALP
- 4-hydroxyalprazolam
- RM
- repeated-measures
- Received December 22, 1998.
- Accepted April 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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