Background/Purpose: Bedtime cyclobenzaprine (CBP) improves fibromyalgia symptoms (pain, fatigue, tenderness, and mood) and improves sleep quality (decreases Cyclic Alternating Pattern Type A2 + A3) (1).  CBP is metabolized by the hepatic P450 isoforms CYP1A1/2 and CYP3A4 into desmethyl, or norcyclobenzaprine (nCBP)(2), but plasma nCBP has only been detected in cases of overdose (3-5). Although CBP has been shown to interact with both the serotonergic (6,7) and noradrenergic (8,9) receptor systems, the functional interactions of CBP with isolated receptors are not fully characterized and those of nCBP are unknown. Therefore, plasma nCBP was measured in healthy subjects after ingesting CBP and the binding and functional activity of CBP and nCBP was studied on a set of CNS targets with potential relevance to CBP actions.

Methods: Plasma CBP and nCBP were measured over 168 hr in ten healthy, fasting subjects who received 5 mg po immediate release CBP HCl.  Equilibrium receptor binding assays were performed on cell lines expressing select recombinant human serotonin, adrenergic, histamine, and muscarinic receptors. Select receptors were analyzed in ligand-induced intracellular Ca⁺mobilization.

Results: The oral bioavailability of CBP was similar to published results (C_max = 4.12 ng mL^-1, t_max = 3.5 h, T_½ = 31.0 h, AUC_0-∞ = 103.1 ng hr mL^-1), but plasma nCBP was unexpectedly high and persistent (C_max = 1.27ng mL^-1, t_max = 24.0 h, T_½ = 72.8 h, AUC_0-∞ = 169.5 ng hr mL^-1).  Unlike CBP, nCBP does not form a stable N⁺-glucuronide, which may affect its clearance.  In vitro, CBP and nCBP exhibited high affinity binding (K_i) to receptors: 5HT2a (5.2 and 13 nM, respectively) and 5HT2c (5.2 and 43 nM), adrenergic α-1A (5.6 and 34 nM), α-2B (K_i = 21 and 150 nM) and α-2C (K_i = 21 and 48 nM,); H1 (1.3 and 5.6 nM); and M1 (7.9 and 30 nM). Like CBP, nCBP is a functional antagonist at 5HT2a (IC₅₀ = 92 nM) by Ca⁺ mobilization.  CBP is also an antagonist on 5HT2b (IC₅₀ = 100 nM). CBP and nCBP are functional antagonists on 5HT2c (IC₅₀ = 0.44 and 1.22 μM) and on α-2A (IC₅₀ = 4.3 and 6.4 μM). In contrast, both CBP and nCBP are functional agonists on 5HT1a (EC₅₀= 5.3 and 3.2 μM).

Conclusion: CBP is metabolized to nCBP which persists in plasma at biologically relevant concentrations after oral CBP in healthy subjects.  CPB and nCBP are potent antagonists of 5HT2a, 5HT2b, H-1, adrenergic α-1A, α-2B and α-2C receptors.  CBP’s antagonist activity on 5HT2b is consistent with the lack of any association with heart valve pathology.  Antagonists of 5HT2a and H-1 are known to have effects on sleep and sleep maintenance.  Adrenergic antagonists may have effects on autonomic dysfunction.  The accumulation of biologically active nCBP without N⁺-glucuronidation may affect responses to CBP therapy in a chronic bedtime dosing regimen.

References: (1) Moldofsky H et al, (2011) J Rheum 38: 2653-2663, (2) Wang R et al, (1996) Drug Metab Dispos 24: 786-791, (3) Hucker HB, et al, (1978) Drug Metab Dispos. 6:659-72 (4) Hucker HB, et al (1977) J Clin Pharmacol. 17:719-27, (5) Wong EC et al, (1995) J Anal Toxicol. 19:218-24, (6) Kobayashi H et al, (1996) Eur J Pharm 311: 29-35, (7) Honda M et al, (2003) Eur J Pharm 458: 91-99, (8) Barnes C et al, (1980) Neuropharm 19: 221-224, (9) Commissiong JW, et al. (1981), Can J Physiol Pharmacol. 59:37-44.

---

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/cyclobenzaprine-cbp-and-its-major-metabolite-norcyclobenzaprine-ncbp-are-potent-antagonists-of-human-serotonin-receptor-2a-5ht2a-histamine-receptor-h-1-and-a-adrenergic-receptors-mechanistic-a/