Benzodiazepines (BZDs) are a class of drugs that are act upon the central nervous system. They are employed clinically as sedatives-anxiolytic drugs (Goodman & Gilman Chapter 16, Katzung Chapter 22); therapy for epilepsies [Article:19674049] (Goodman & Gilman Chapter 19, Katzung Chapter 24); panic disorders (Goodman & Gilman Chapter 17) and various other disorders. BZDs share the common substructure of a benzene ring fused to a diazepine ring, a seven-membered heterocylic molecule with 2 nitrogens (Goodman & Gilman Chapter 16). Since all the important benzodiazepines contain a 5-aryl substituent (ring C) and a 1,4-diazepine ring, the term has come to mean the 5-aryl-1,4-benzodiazepines (Goodman & Gilman Chapter 16, Katzung Chapter 22). Modifications to this basic substructure exist; but we will restrict the discussion to those drugs with this basic template, as well as to those used in treatment of central nervous disease disorders. There are more than 20 drugs in this class that are used in central nervous system disorders; a partial list can be seen by clicking on the Benzodiazepine icon in the pathway above. Because of the large number of drugs in this class, this summary is not meant to be exhaustive but, rather, a highlight of the important genes in the benzodiazepine pathway.
The primary target of BZDs is the GABAa receptor, a ligand-gated ion (chloride) channel, activated by gamma-aminobutyric acid (GABA) [Articles:11689393, 751612, 18384456] (Goodman & Gilman Chapter 16). The GABAa receptor is a pentameric assembly of homologous GABAa receptor subunits [Articles:11689393, 751612] (Goodman & Gilman Chapter 16, Katzung Chapter 22). Please see the benzodiazepine pharmacodynamics pathway for more details.
While the BDZs share a common template, they have different physiochemical properties, most notably lipid solubility, which influence their pharmacokinetics, as well as their rate of absorption and diffusion [Article:18384456]. Benzodiazepines relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue [Articles:1968714, 9824847]. The two principal pathways of the BDZ biotransformation involve hepatic microsomal oxidation, N-dealkylation or aliphatic hydroxylation and glucuronide conjugation [Article:18175099] (Katzung Chapter 22). The metabolites are excreted mainly by the kidney (Katzung Chapter 22). Many hydroxylated metabolites of BDZs are pharmacologically active, some with long half-lives. (Katzung Chapter 22, Goodman & Gilman Chapter 16). The specific enzymes involved in the hydrozylation vary, but are primarily CYP3A4 and CYP3A5 and CYP2C19 , although some studies have found that other CYP enzymes are involved [Articles:18855614, 17636336, 18384456]. Phase I and phase II metabolizing enzymes of the various BDZs are depicted in the PK pathway image. Because of space limitations, we have only included a subset of all the BDZs. Glucuronidation occurs via UGT [Articles:18855614, 12386133]; in particular, UGT1A4 catalyzes the N-glucuronidation of midazolam [Articles:18256203, 18855614]; UGT2B15 catalizes the glucuronidation of S-oxazepam [Article:12386133]; UGT2B7 and UGT1A9 catalyzes the glucuronidation of R-oxazepam [Article:12386133]. Acetylation of clonazepam has been reported to occur via NAT2 [Articles:19356010, 7273597].
Because many drugs are metabolized by and inhibit CYP3A4/5 and CYP2C19, there may be drug-drug interactions (DDIs) for many BZDs. Midazolam, in particular (and ketoconazole) are extensively used both in vitro and in vivo for the prediction of CYP3A-mediated DDIs [Article:18256203]. One FDA tablet insert for midazolam indicated that inhibitors of CYP3A4, such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil, were shown to significantly increase the Cmax and AUC of orally administered midazolam; and that cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, can cause a markedly decreased Cmax and AUC of oral midazolam (please see the midazolam DailyMed drug label). For diazepam, one FDA tablet insert for diazepam indicated that there is a potentially relevant interaction between diazepam and compounds which inhibit CYP3A and CYP2C19 that may lead to increased and prolonged sedation; these drugs include cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole (please see the diazepam DailyMed drug label).
Benzodiazepines as inhibitors:
There are a few studies of BDZs as inhibitors. One study found that flurazepam, a positively charged BDZ, inhibits SLC22A2 [Article:19251820]. Another study found that flunitrazepam, a competitive inhibitor of morphine glucuronidation in hepatic microsomes, competitively inhibited catechol estrogen glucuronidation catalyzed by UGT2B7*2 (rs7439366 NM_001074.2:848T>C), UGT1A1, and UGT1A3 [Article:9848110]. An in vitro study found that bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam, midazolam, and nitrazepam inhibited CYP2E1 at micromolar concentrations [Article:9574817] .
Pharmacogenomics studies of BDZs have focused on their metabolizing enzymes. A review of the effects of genetic polymorphisms of CYP3A4, CYP3A5, and CYP2C19 on BDZs has recently been published [Article:17635335].
CYP3A4 and CYP3A5
The impact of polymorphisms in CYP3A4 and CYP3A5 on different BDZ metabolism have been mixed. Several in vitro and in vivo studies showed that genetic variations in CYP3A4 and CYP3A5 did not contribute to large inter-individual variability in midazolam hydroxylation or disposition [Articles:16638818, 15900284]. On the other hand, one in vitro study using midazolam indicated that CYP3A4*16 (rs12721627 NM_017460.3: 658:C>G Thr185Ser, commonly referred to as 554C>G ) showed substrate-dependent altered kinetics compared with (wild type) CYP3A4*1 [Article:19255940] and another small (n=7) in vivo study of alprazolam showed that oral clearance was significantly different between the (wild type) CYP3A5*1 individuals vs. the CYP3A5*3 individuals [Article:16765147]. Also, in a study of 63 Japanese patients emerging from anesthesia, researchers found that the slow-emergence group possesses lower levels of CYP3A4 mRNA than found in the rapid-emergence group [Article:16338280].
While the BDZs share a common template, and all bind to the GABAa receptor, they have different physiochemical properties, most notably lipid solubility, which influence their pharmacokinetics, as well as their rate of absorption and diffusion [Article:18384456]. The two principal pathways of the BDZ biotransformation involve hepatic microsomal oxidation, N -dealkylation or aliphatic hydroxylation and glucuronide conjugation [PMID: 18175099 (Katzung Chapter 22). Pharmacogenomics studies of BDZs have focused on their metabolizing enzymes.
Unlike the case of CYP3A4/5, polymorphisms of CYP2C19 appear to have an impact on the metabolism of several BDZs. Studies found that poor metabolizers had significantly lower plasma clearance of both diazepam [Articles:2495208, 1505151] and desmethydiazepam [Articles:2495208, 1505151] when compared to extensive metabolizers. Similarly, for poor metabolizers, diazepam had longer plasma half-life [Article:2225709] and etizolam had a longer elimination half-life [Article:16261363] when compared to extensive metabolizers. And, in a study of 63 Japanese patients emerging from anesthesia, researchers found that the CYP2C19 genotype affected diazepam pharmacokinetics and emergence from general anesthesia [Article:16338280].
Based on the level of NAT2 acetylator activity, individuals in human populations are divided into three enzymatic phenotypes: rapid (normal activity), intermediate and slow (reduced activity) [Articles:1066746, 28606751]. A small, early in vivo study found that rate of acetylation of clonazepam was dependent upon acetylator phenotype (7273597). One in vitro study found that 2 variant haplotypes NAT2*5B (composed of 3 variants: rs1801280 NM_000015.2:448T>C, commonly referred to as 341T>C ; rs1799929 NM_000015.2 :588C>T, commonly referred to as 481C>T; and rs1208 NM_000015.2:910G>A, commonly referred to as 803A>G) and NAT2*6A (composed of 2 variants: rs1041983 NM_000015.2:389C>T commonly referred to as 282C>T; and rs1799930 NM_000015.2:697G>A commonly referred to as 590G>A) caused a 20 and 22-fold reduction, respectively, in the Vmax of the acetylation reaction of clonazepam [Article:19356010], consistent with other studies that show these haplotypes have the 'slow acetylator' phenotype (please see the NAT nomenclature website).
The Tyr variant of UGT2B15*2 (rs1902023, frequently referred to as Asp85Tyr variant) was found to be a major determinant of inter-individual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam (N=24, Korean subjects) [Article:15961980]. In addition, gender and the same UGT2B15 (Tyr) variant rs1902023, as well as gender, were identified as major determinants of S-oxazepam glucuronidation by the human liver [Article:15044558].
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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Entities in the Pathway
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|diazepam||nordazepam||CYP2C19, CYP3A4||17635335, 18855614|
|hydroxymidazolam||Glucoronidation||UGT1A4, UGT2B4, UGT2B7||18855614|
|midazolam||hydroxymidazolam||CYP3A4, CYP3A5||17635335, 18855614|
|oxazepam||Glucoronidation||UGT1A9, UGT2B15, UGT2B7||12386133|
|triazolam||hydroxytriazolam||CYP3A4, CYP3A5||17635335, 18855614|
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