A Double-Peak Phenomenon in the Pharmacokinetics of Alprazolam after Oral Administration

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 doublepeak 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 (a-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. Alprazolam (ALP), 1 a triazolobenzodiazepine, is the most widely prescribed benzodiazepine (BZ) and is used as an anxiolytic, antipanic, and antidepressant agent (Fawcett and Kravitz, 1982; Dawson et al., 1984). In humans, ALP is rapidly and completely absorbed after oral administration, with an elimination half-life of 6 to 16 h and volume of distribution of 1 l/kg, respectively (Greenblatt et al., 1983; Smith et al., 1984; Garzone and Kroboth, 1989). ALP is extensively metabolized in humans; the two active metabolites, a-hydroxyalprazolam (a-OHALP) and 4-hydroxyalprazolam (4-OHALP), are ;60 and 20% as potent as ALP (Sethy and Harris, 1982). In rats, ALP was rapidly eliminated with a terminal half-life of ;40 min (Lau et al., 1997a). Although ALP has been administered orally to rats (Owens et al., 1991; Lau et al., 1997b), there is a lack of information on its oral pharmacokinetics (PK) and bioavailability. This investigation was undertaken to characterize the serum ALP concentration-time profiles after oral ALP doses. The study was designed to be conducted in animals that are of the same species, age, and gender as well as under the same food-limited regimen used in our previous studies for PK of s.c. and i.p. ALP (Lau and Wang, 1996; Lau et al., 1997; Lau and Heatherington, 1997) so that comparison could be made across route of administration. Here we report a double-peak phenomenon in serum concentrationtime profiles of ALP via oral administration. Similar doubleand multiple-peak phenomena have been described for many structurally diverse compounds such as acebutolol, veralipride, and danazol after oral doses (Plusquellec et al., 1987; Charman et al., 1993; PiquetteMiller and Jamali, 1997), but such phenomenon has not been reported for BZs. Materials and Methods Animals. Four male, albino, Sprague-Dawley rats from Harlan SpragueDawley, Inc. (Indianapolis, IN) were used. They were housed individually in a temperature-regulated room with a daily cycle of illumination from 7:00 AM to 7:00 PM. They were reduced to 80% of their initial, adult free-feeding body weights (mean5 381 g; range: 380–382 g) by receiving limited daily food rations (5 g for the first day, 10 g for the next 5 days) and were then maintained at their weights with a daily food supplement (range: 14–16 g). Water was continuously available in the living cages. They were held at these weights for 2 to 3 months before starting the experiment, a time period usually needed for training, establishing baseline, and examining drug dose-response relations for operant behavior. Experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication 85-23, revised 1985). This research was supported by National Institute on Drug Abuse Grant R37 DA03117 (J.L.F.). 1 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 which C1max occurred; T2max, time at which C2max occurred; Tmin, time at which Cmin occurred; Vc, volume of distribution in the central compartment; Vss, volume of distribution at steady state; a-OHALP, a-hydroxyalprazolam; 4-OHALP, 4-hydroxyalprazolam; RM, repeated-