The relationship between chemical structure and the in vivo metabolism of an homologous series of n-alkyl carbamates

Abstract

The metabolism and pharmacokinetics of carbonyl [14C] labelled ethyl, n-butyl, n-hexyl and n-octyl carbamates has been examined in rats after oral and intravenous administration. Hydrolysis of the carbamate group was a major metabolic fate, particularly of the more water soluble carbamates. Conversely, with increasing lipophilicity increasing amounts of omega-1 oxidation products were found both in plasma and urine. The plasma pharmacokinetic data could not be explained by a simple bi-exponential model, ethyl carbamate in particular showing unexpectedly persistent blood levels. A model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential features of this model are that carbamate is thought not to be in equilibrium between the peripheral and central compartment and that hydrolytic metabolism takes place in the peripheral compartment while oxidative metabolism to urinary metabolites occurs in the central compartment.

Acyl, N-protected .alpha.-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide

“…L-HpGlu-L-Leu-NHCN (19) and L-HpGlu-L-Phe-NHCN (20) were readily prepared by coupling of L-HpGlu-L-Leu and L-HpGlu-L-Phe with sodium cyanamide via their respective IV-hydroxysuccinimide activated esters. However, 19 and L-pyroglutamylcyanamide itself (21) could not be obtained in pure form.…”

“…L-HpGlu-L-Leu-NHCN (19) and L-HpGlu-L-Phe-NHCN (20) were readily prepared by coupling of L-HpGlu-L-Leu and L-HpGlu-L-Phe with sodium cyanamide via their respective IV-hydroxysuccinimide activated esters. However, 19 and L-pyroglutamylcyanamide itself (21) could not be obtained in pure form. That 21 might be unstable was indicated by the observation that IV-carbobenzoxy-Lpyroglutamylcyanamide (22), a stable crystalline solid, when subjected to catalytic hydrogenolysis with H2/Pd gave a mixture of multiple products, which discouraged further attempts to prepare 21.…”

“…Z-Gly-L-Leu-NHCN (18) Z-L-pGiu-NHCN (22) L-HpGIu-L-Leu-NHCN (19) L-HpGIu-L-Phe-NHCN (20) 0 400 800 1200 1600 2000…”

“…glutamyl-L-leucyl- (19), and L-pyroglutamyl-L-phenylalanylcyanamide (20). All of these prodrugs of cyanamide raised ethanol-derived blood acetaldehyde levels in rats significantly over controls 3 h after ip drug administration, and some of these were still capable of elevating blood acetaldehyde 16 h post drug administration.…”

“…Although 1 does not inhibit A1DH in vitro,11 doses of 1.0 mmol/kg administered to rats raised ethanol-derived blood AcH levels 25-fold over control values, a result that constitutes pharmacological evidence that some cyanamide must have been liberated in vivo.12 *Indeed, administration of [l-14C]acetyl-labeled 1 to rats gave rise to the excretion of nearly 2% of the administered radioactive dose as [14C]C02 within 8 h, thereby providing corroborative bio-chemical evidence that finite deacetylation of 1 to cyanamide had taken place.12 On the basis of these results, several acyl derivatives of cyanamide were synthesized specifically as prodrug forms, including benzoylcyanamide (2), the sterically bulky pivaloylcyanamide (3) and 1adamantoylcyanamide (4) ostensibly to retard the rate of enzymatic hydrolysis of the acylcyanamide linkage, and lipophilic long-chain fatty acyl derivatives such as palmitoylcyanamide (6) and stearoylcyanamide (7) to prevent rapid renal excretion, with n-butyrylcyanamide (5) and phenylacetylcyanamide (Na salt,23) cyanamide (Z-Gly-NHCN, 10), hippurylcyanamide (Bz-Gly-NHCN, 13), IV-benzoyl-L-leucylcyanamide (Bz-l-Leu-NHCN, 14), iV-carbobenzoxyglycyl-L-leucylcyanamide (Z-Gly-L-Leu-NHCN, 18), IV-carbobenzoxy-L-pyroglutamylcyanamide (Z-L-pGlu-NHCN, 22), L-pyroglutamyl-L-leucylcyanamide (L-HpGlu-L-Leu-NHCN, 19), and L-pyroglutamyl-L-phenylalanylcyanamide (L-HpGlu-L-Phe-NHCN, 20), all of which are based on the potential for peptidase action for the ultimate cleavage of the acylcyanamide linkage in vivo.…”