A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. (1/117)

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 (alpha-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 approximately 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.  (+info)

Quantitation of alprazolam and alpha-hydroxyalprazolam in human plasma using liquid chromatography electrospray ionization MS-MS. (2/117)

A sensitive and specific electrospray ionization high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method has been developed for the quantitative determination of alprazolam (AL) and alpha-hydroxyalprazolam (OH-AL) in plasma. After the addition of deuterium labeled internal standards of AL and OH-AL, plasma samples were buffered to alkaline pH and extracted with toluene/methylene chloride (7:3). Dried extract residues were reconstituted in HPLC mobile phase and injected onto a reversed-phase C18 HPLC column. The analytes were eluted isocratically at a flow rate of 250 microL/min using a solvent composed of methanol and water (60:40) containing 0.1% formic acid. The analyses were performed using selected reaction monitoring. The assay was sensitive to 0.05 ng/mL for both the parent drug and metabolite and linear to 50 ng/mL. The intra-assay percent coefficients of variation (%CV) for AL at 2, 5, and 20 ng/mL were all < or = 5.6. At these concentrations, and all OH-AL intra-assay %CVs were < or = 8.4. The interassay variabilities for AL were 11.8%CV, 8.7%CV, and 8.7%CV at 2.0, 5.0, and 20.0 ng/mL, respectively. The OH-AL interassay variabilities were 9.6%CV, 9.2%CV, and 7.8%CV at the same concentrations, respectively. The assay accuracy was less than or equal to +/- 6.6% for both analytes at the three concentrations. The method was used to quantitate AL and OH-AL in plasma samples collected from 10 subjects who were administered a 1-mg oral dose of AL. The mean AL concentration peaked at 11.5 ng/mL 1 h after the dose and AL was detectable for 48 h. The mean OH-AL concentration peaked at 0.18 ng/mL 4 h after the dose and was undetectable by 36 h. Hydrolysis of the plasma samples had little effect on the detected AL concentrations but increased OH-AL concentrations substantially. Plasma/blood ratios for AL and OH-AL exceeded 1 in the study samples.  (+info)

Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. (3/117)

In view of the substantial preclinical evidence that supports a seminal role of central corticotropin-releasing factor (CRF) neuronal systems in the physiology and pathophysiology of stress and anxiety, it is reasonable to suggest that the anxiolytic properties of benzodiazepines are mediated, at least in part, via regulation of CRFergic function. To begin to test this complex hypothesis, we examined the effects of acute and chronic administration of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor-binding density, and mRNA expression in the CNS. Additionally, we measured mRNA expression for urocortin, a recently discovered neuropeptide that is generally considered to be a second endogenous ligand for CRF receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the basolateral amygdala. In marked contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and ventromedial hypothalamus were increased. Similar findings of an inverse relationship between the CRF(1) and CRF(2A) receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, subdivisions that can be coordinately and inversely regulated by stress, anxiety, or anxiolytic drugs.  (+info)

Effects of age on in vitro midazolam biotransformation in male CD-1 mouse liver microsomes. (4/117)

To study age-related changes in drug metabolism, we examined the in vitro biotransformation of midazolam (MDZ), a human cytochrome P-450 (CYP) 3A substrate, using liver microsomes from three age groups of male CD-1 mice ranging from 6 weeks to 2 years old. MDZ was metabolized to two major products, alpha-OH- and 4-OH-MDZ, which were quantified by HPLC. For both metabolites, V(max) values were reduced in old livers (P <.05), while K(m) values did not change with age. The net intrinsic clearance (the sum of V(max)/K(m) for both pathways) also was reduced in the old animals (P <.05). The capacity of ketoconazole, a CYP3A inhibitor in humans, to inhibit the biotransformation of MDZ and of alprazolam, another human CYP3A substrate, did not differ significantly with age. At 100 microM alprazolam, 0.5 microM ketoconazole inhibited metabolite formation by >80%. At 30 microM MDZ, 2.5 microM ketoconazole impaired 4-OH-MDZ formation by 88%, whereas it reduced alpha-OH-MDZ formation by only 46%. Immunoinhibition studies with polyclonal anti-rat CYP3A1/2 and CYP2C11 antibodies confirmed that 4-OH-MDZ formation was largely CYP3A-dependent, while alpha-OH-MDZ formation was mediated by CYP3A and -2C isoforms. Western blot analysis revealed decreased microsomal content of CYP3A in old livers. Net intrinsic clearance of MDZ was correlated with total CYP3A content (P <.001). These results demonstrate a reduction in MDZ biotransformation in old male mice, which may be attributable, in part, to decreased CYP3A content in old livers. Changes in expression and activity of CYP2C isoforms also may contribute to age-related changes in MDZ biotransformation, but this requires more investigation.  (+info)

Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance. (5/117)

The partial allosteric modulators (PAMs) of gamma-aminobutyric acid-gated Cl(-) current intensities at gamma-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition.  (+info)

A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat. (6/117)

The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound [(1S,3aS)-8- (2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza- spiro[4. 5]decan-4-one] has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg/kg i.p.). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (>/=10 mg/kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ/nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ/nociceptin in adaptive behavioral fear responses to stress.  (+info)

Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general. (7/117)

Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.2 microg/mL in humans. The effects of competitive inhibition can be divided into two components: first-pass hepatic metabolism and systemic metabolism. For drugs with high hepatic extraction ratios, the impact of competitive inhibition on hepatic first-pass metabolism can be particularly dramatic. For example, human terfenadine hepatic extraction goes from 95% in the absence of a competitive inhibitor to 35% in the presence of one (ketoconazole, 200 mg po Q 12 h dosed to steady-state). First-pass extraction therefore goes from 5% in the absence of the inhibitor to 65% in its presence. The combined effect on first-pass and systemic metabolism produces an approximate 37 fold increase in terfenadine area under the plasma concentration-time curve. Assuming intact drug is active and/or toxic, development of metabolized drugs with extensive first-pass metabolism should be avoided if possible, since inhibition of metabolism may lead to profound increases in exposure.  (+info)

Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors. (8/117)

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.  (+info)

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