Metabolism

Biotransformation of the benzodiazepines occurs in the liver. The two principal pathways involve either hepatic microsomal oxidation (N-dealkylation or aliphatic hydroxylation) or glucuronide conjugation.^{[352] [365]} The difference in the two pathways is significant because oxidation is susceptible to outside influences and can be impaired by certain population characteristics (e.g., old age), disease states (e.g., hepatic cirrhosis), or the coadministration of other drugs that can impair oxidizing capacity (e.g., cimetidine). Conjugation is less susceptible to these factors.^[352] Both midazolam and diazepam undergo oxidation reduction or phase I reactions in the liver.^[366] The fused imidazole ring of midazolam is oxidized rapidly by the liver, much more rapidly than the methylene group of the diazepine ring in other benzodiazepines. This rapid oxidation accounts for the greater hepatic clearance of midazolam than diazepam. Lorazepam is less affected by enzyme induction and some of the other factors known to alter the cytochrome P450 and other phase I enzymes. For example, inhibition of oxidative enzyme function by cimetidine impairs the clearance of diazepam,^[367] but it has no effect on lorazepam.^[366] Age decreases and smoking increases the clearance of diazepam,^[34] but neither has a significant effect on midazolam biotransformation.^[21] Habitual alcohol consumption increases the clearance of midazolam.^[368] Race, because of differences in the isoenzymes responsible for hydroxylation, produces genetic differences in drug metabolism.^[369] The high frequency of mutated alleles in Asians in the genes coding for CYP2C19

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The metabolites of benzodiazepines can be important. Diazepam forms two active metabolites, oxazepam and desmethyldiazepam, both of which add to and prolong the drug's effects. Midazolam is biotransformed to hydroxymidazolams, which have activity and, when given over a longer time, can accumulate.^[370] However, these metabolites are rapidly conjugated and excreted in urine. 1-Hydroxymidazolam has an estimated clinical potency that is 20% to 30% that of midazolam.^[35] It is excreted largely by the kidneys and can cause profound sedation in patients with renal impairment.^[36] The primary hydroxymetabolite is cleared more rapidly^[35] than midazolam in healthy patients ( Table 10-8 ). Thus, the metabolites are less potent and normally cleared more rapidly than midazolam, so they are of little concern in patients with normal hepatic and renal function. Lorazepam has five metabolites, but the principal one is conjugated to glucuronide. This metabolite is inactive, water soluble, and rapidly excreted by the kidney.