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Pharmacokinetics of the Newer Benzodiazepines

  • Review Article
  • Drug Disposition
  • Published:
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Summary

The assay methods used to determine the concentrations of the newer benzodiazepines include electron-capture gas-liquid chromatography, high performace 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 α1-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, α-hydroxyalprazolam, has pharmacological activity. α-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. α-Hydroxytriazolam is the major metabolite, in addition to which 4-hydroxyalprazolam and α-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.

Factors such as age, gender, and obesity can influence the pharmacokinetics of alprazolam and triazolam. The reported drug-drug interactions with both agents are predominantly the result of inhibition of the microsomal enzyme system responsible for the hepatic metabolism and elimination of these benzodiazepines.

Midazolam and loprazolam are basic compounds; the imidazole ring allows for the preparation of aqueous injectable solutions that are stable and well tolerated. Both drugs are rapidly absorbed after oral administration. Peak midazolam concentrations occur in 20 to 60 minutes, while peak loprazolam concentrations are reached in 0.5 to 2 hours. Bioavailability of oral midazolam ranges from 34 to 68%. It is also rapidly absorbed after intramuscular administration, and the bioavailability then ranges from 40 to 100%. The absolute bioavailability of loprazolam in man has not been reported; however, approximately 70 to 75% of the oral dose is absorbed in animals.

The volume of distribution for both midazolam and loprazolam is large, 0.5 to 3 L/kg, with great intersubject variability. The plasma protein binding of midazolam is 95%, while loprazolam is 80% protein bound.

Midazolam undergoes hydroxylation and subsequent glucuronidation. The elimination half-life of midazolam is approximately 2 hours; however, there have been reports of prolonged elimination (> 8 hours) in subpopulations of subjects. The elimination half-life of α-hydroxymidazolam, the major midazolam metabolite, is approximately 1 hour.

Loprazolam is not as rapidly metabolised as midazolam. The major elimination pathway is N-oxidation of the piperazine ring. Depending on the assay method, the elimination half-life for loprazolam has ranged between 4 and 15 hours. The longer half-life may reflect the activity of metabolites, with the actual value being between 4 and 7 hours. The most common type of drug-drug interaction reported for midazolam also involves the inhibition of the microsomal mixed function oxidase system responsible for the metabolism of that drug. Loprazolam interactions have not been extensively studied.

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Garzone, P.D., Kroboth, P.D. Pharmacokinetics of the Newer Benzodiazepines. Clin-Pharmacokinet 16, 337–364 (1989). https://doi.org/10.2165/00003088-198916060-00002

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