How is clonazepam (Klonopin) metabolized in the body?

Clonazepam Metabolism

Primary Metabolic Pathway

Clonazepam is highly metabolized in the liver with less than 2% excreted unchanged in the urine, primarily through reduction of the 7-nitro group to the 4-amino derivative, which then undergoes acetylation, hydroxylation, and glucuronidation. 1

• The biotransformation occurs mainly by reduction of the 7-nitro group to form the 4-amino derivative, which can subsequently be acetylated, hydroxylated, and glucuronidated 1
• Cytochrome P450 enzymes, including CYP3A4, play an important role in clonazepam reduction and oxidation 1
• Human studies using liver microsomes demonstrate that P450 3A4 (nf25) is the primary isozyme involved in clonazepam nitroreduction, with significant correlation between P450 3A4 gene expression and clonazepam metabolism intensity 2

Pharmacokinetic Properties

• Clonazepam is rapidly and completely absorbed after oral administration with approximately 90% absolute bioavailability 1
• Maximum plasma concentrations are reached within 1 to 4 hours after oral administration 1
• The drug is approximately 85% bound to plasma proteins 1
• The elimination half-life is typically 30 to 40 hours, making it a long-acting benzodiazepine 3, 1
• Clonazepam pharmacokinetics are dose-independent throughout the dosing range 1
• There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans 1

Clinical Implications for Hepatic Disease

Because clonazepam undergoes extensive hepatic metabolism, liver disease will likely impair clonazepam elimination, requiring caution when administering to patients with hepatic dysfunction. 1

• The FDA label specifically notes that liver disease is expected to impair elimination, though controlled studies have not been conducted 1
• This contrasts with benzodiazepines like lorazepam that undergo direct glucuronide conjugation and are less affected by hepatic impairment 4

Renal Considerations

• Controlled studies examining the effects of renal disease on clonazepam pharmacokinetics have not been conducted 1
• Since clonazepam and its metabolites are primarily eliminated through the kidneys after hepatic metabolism, renal insufficiency may affect clearance, though the extent is not well-characterized 1

Pediatric Metabolism

• In children, clearance values of 0.42 ± 0.32 mL/min/kg (ages 2-18 years) and 0.88 ± 0.4 mL/min/kg (ages 7-12 years) have been reported 1
• These clearance values decrease with increasing body weight 1
• Ketogenic diet in children does not affect clonazepam concentrations 1

Drug Interaction Potential

• As a substrate of CYP3A4, clonazepam metabolism may be affected by CYP3A4 inhibitors (azole antifungals, macrolide antibiotics, calcium antagonists, grapefruit juice) or inducers (antiepileptics, rifampicin) 5
• However, clonazepam is only partly metabolized by CYP3A4 (unlike alprazolam, triazolam, brotizolam, and midazolam which are mainly metabolized by this enzyme), suggesting a lower potential for clinically significant drug interactions compared to other benzodiazepines 5

Common Pitfalls

• Do not assume clonazepam can be dosed normally in severe hepatic disease—dose reduction or alternative agents should be strongly considered 1
• The long half-life (30-40 hours) means steady-state is not reached for approximately 5-7 days, and drug accumulation can occur with repeated dosing 3, 1
• Unlike some benzodiazepines, clonazepam's mechanism of action in REM sleep behavior disorder does not involve normalization of REM atonia, but rather preferential control of phasic locomotor activity at the brainstem level, possibly via serotonergic effects 3