Pharmacokinetics of the Newer Benzodiazepines

Abstract

The assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performance liquid chromatography with ultraviolet detection, gas chromatography-mass spectrometry, radioassay and radioreceptor assay. The method used frequently is the highly sensitive and specific electron-capture gas-liquid chromatography. Other methods are associated with limitations. The triazolo- and imidazolebenzodiazepines differ structurally from the 'classical' benzodiazepines such as diazepam, and offer distinct differences in pharmacological activity and in time-course of effect. Alprazolam and triazolam, both 1,4-triazolobenzodiazepines, have high affinities for the benzodiazepine receptor as do midazolam and loprazolam, which are 1,4-imidazolebenzodiazepines. Absorption is characteristically rapid, with peak alprazolam and triazolam concentrations occurring within 1 hour after oral administration. Sublingual administration results in peak alprazolam and triazolam concentrations that are higher and occur earlier than with the oral route. The volume of distribution of alprazolam and triazolam is approximately 1L. Alprazolam is 70% bound to plasma proteins and the extent of binding is independent of concentration. Similarly, triazolam is approximately 85% bound to plasma proteins, variability in binding being explained by variations in alpha 1-acid glycoprotein concentration. The 1,4-triazolo ring prevents the oxidative metabolism of the classical benzodiazepines which results in formation of active metabolites with long elimination half-lives. Alprazolam is extensively metabolised: 29 metabolites have been identified in the urine, and its major metabolite, alpha-hydroxyalprazolam, has pharmacological activity. alpha-Hydroxyalprazolam and 4-hydroxyalprazolam are detectable in plasma in amounts which account for less than 10% of the administered dose. Mean alprazolam elimination half-life in healthy adult subjects ranges from 9.5 to 12 hours; liver disease prolongs alprazolam elimination, but renal insufficiency does not. Triazolam also undergoes oxidation and subsequent glucuronidation. alpha-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and alpha-4-hydroxytriazolam have been identified in plasma and urine. The elimination half-life of triazolam ranges between 1.8 and 5.9 hours, while that of the conjugated metabolites is short, approximately 3.8 hours. Accumulation of triazolam or its metabolites after multiple doses does not occur. Liver disease prolongs triazolam elimination from the body, but renal disease does not.(ABSTRACT TRUNCATED AT 400 WORDS)

The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions

“…The amount of CYP3A in the intestine has been reported to be approximately 1% of that in the liver (Thummel et al, 1997;Yang et al, 2004). For all of the CYP3A probe substrates, a value for f m(CYP3A) was assumed to be 0.93, with the exception of alprazolam in which a value corrected for the percentage excreted unchanged in urine of 20% (Garzone and Kroboth, 1989) was accounted for yielding a value for f m(CYP3A) of 0.74. The 0.93 values were estimated by assuming that 400 mg/day of ketoconazole causes complete inhibition of CYP3A in vivo and that the remaining capability to clear these drugs is via other processes.…”

Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.

“…Water (1 ml) was added to the remaining supernatant and then loaded into a Bond Elut CN solid-phase extraction cartridge (Varian®, Harbour City, CA), which had been preactivated with 2 ml methanol followed by 2 ml Milli-Q water. The cartridge was rinsed with 1 ml Milli-Q water and centrifuged for 1 Four recently published models have been proposed to predict the distribution of drugs between milk and plasma. Predicted M/S value (M/Spred) can be calculated from the in vitro physicochemical properties of the drug, assuming a passive simple diffusion.…”

“…The incidence of psychiatric illness is higher in the life resulting in less cumulative drowsiness [1,2]. It first 12 weeks of postpartum than at any other time in is commonly prescribed for the treatment of general-a women's life [5].…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…63). The metabolite is present at far lower concentrations in plasma (Smith and Kroboth, 1987;Garzone and Kroboth, 1989) and it is thus unlikely to contribute significantly to the pharmacological effects of alprazolam.…”