Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

Abstract

Glucuronidation is an important mechanism used by mammalian systems to clear and eliminate both endogenous and foreign chemicals. Many functional groups are susceptible to conjugation with glucuronic acid, including hydroxyls, phenols, carboxyls, activated carbons, thiols, amines, and selenium. Primary and secondary amines can also react with carbon dioxide (CO(2)) via a reversible reaction to form a carbamic acid. The carbamic acid is also a substrate for glucuronidation and results in a stable carbamate glucuronide metabolite. The detection and characterization of these products has been facilitated greatly by the advent of soft ionization mass spectrometry techniques and high field NMR instrumentation. The formation of carbamate glucuronide metabolites has been described for numerous pharmaceuticals and they have been identified in all of the species commonly used in drug metabolism studies (rat, dog, mouse, rabbit, guinea pig, and human). There has been no obvious species specificity for their formation and no preference for 1 degrees or 2 degrees amines. Many biological reactions have also been described in the literature that involve the reaction of CO(2) with amino groups of biomolecules. For example, CO(2) generated from cellular respiration is expired in part through the reversible formation of a carbamate between CO(2) and the alpha-amino groups of the alpha- and beta-chains of hemoglobin. Also, carbamic acid products of several amines, such as beta-N-methylamino-L-alanine (BMAA), ethylenediamine, and L-cysteine have been implicated in toxicity. Studies suggested that a significant portion of amino-compounds in biological samples (that naturally contain CO(2)/bicarbonate) can be present as a carbamic acid.

Species Differences in the Biotransformation of an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist: The Effects of Distinct Glucuronide Metabolites on Overall Compound Disposition

“…In MLMs (ϮNADPH), [ 14 C]1 was also inert. Although subjecting [ 14 C]1 to MLMs optimized for N-carbamoyl glucuronidation was not conducted, MLMs are typically capable of producing RLM-observed N-carbamoyl glucuronides (Schaefer, 2006). To explore further qualitatively the selective formation of M5 in monkeys, 1 (1 M) was incubated in monkey hepatocytes.…”

Pharmacokinetics and Metabolism of an .ALPHA.,.BETA.-Blocker, Amosulalol Hydrochloride, in Mice: Biliary Excretion of Carbamoyl Glucuronide

“…16) Subsequently, reports on the formation of various carbamoyl glucuronides by primary and secondary amines were published (recently reviewed by Schaefer). 17) It has been proposed that the mechanism that generates these glucuronides starts by forming carbamic acid as an intermediate under physiological conditions in the liver through a reversible reaction with CO 2 dissolved in the environmental fluid. 13,[18][19][20][21][22] UDP-glucuronyl transferase (UGT) then causes the immediate conjugation of this carbamic acid with glucuronic acid by utilizing UDPglucuronic acid as a cofactor.…”

Metabolism and Excretion of Asenapine in Healthy Male Subjects

“…It is not unreasonable to propose that the carbamic acid of asenapine serves as the transiently formed intermediate for glucuronidation. For several drugs containing a primary, secondary, or tertiary amine, the formation of a carbamic acid followed by glucuronidation has been observed (Ronfeld et al, 1982;Straub et al, 1988;Brown et al, 1990;Delbressine et al, 1990;Obach et al, 2005Obach et al, , 2006Schaefer, 2006). An unprotonated primary or secondary amine and CO 2 are required to form a carbamic acid , which was subsequently conjugated with the glucuronic acid (Schaefer, 2006).…”

“…For several drugs containing a primary, secondary, or tertiary amine, the formation of a carbamic acid followed by glucuronidation has been observed (Ronfeld et al, 1982;Straub et al, 1988;Brown et al, 1990;Delbressine et al, 1990;Obach et al, 2005Obach et al, , 2006Schaefer, 2006). An unprotonated primary or secondary amine and CO 2 are required to form a carbamic acid , which was subsequently conjugated with the glucuronic acid (Schaefer, 2006). The formation of a carbamate glucuronide has been observed in excreta or in the circulatory system of several species, including humans, for several drugs, including tocainide (Ronfeld et al, 1982), sertraline (Obach et al, 2005), rimantadine (Brown et al, 1990), and varenicline (Obach et al, 2006).…”