Abstract
A series of n-alkyl carbamates has been used to characterize the role of lipophilicity in drug absorption, binding to cytochrome P[450] and metabolism. It was found that the rate of absorption of these carbamates from the urinary bladder was comparable to that from the small intestine; it reached a plateau for the more lipophilic carbamates. Addition of the non-ionic detergent Tween 80 as a solubilizing agent reduced the rate of absorption of n-octyl carbamate but not that of ethyl carbamate; it was shown that this was probably due to the formation of an additional luminal hydrophilic barrier to absorption, Sargent et al, 1979; Bridges et al, 1979. Affinity of binding of the n-alkyl carbamates to cytochrome P[450] in isolated viable suspension of adult rat hepatocytes was found to be directly dependent upon lipophilicity. All the carbamates gave type I binding spectra within one second of addition of substrate. Since binding to P[450] is the first requisite for the oxidative metabolism of most xenobiotics, the latter finding suggests that rate of access to cytochrome P450 did not limit the rate of metabolism. The extent of metabolism in isolated hepatocytes was also found to depend on lipophilicity. No metabolism of the aliphatic group of ethyl carbamate was apparent whilst the higher members of the series gave rise to two major metabolites. These were tentatively identified by chemical ionization mass spectroscopy for n-hexyl carbamate after in vivo incubation as the (o - 1) hydroxylation product and its further oxidation product, the ketone. Covalent binding to cell constituents was not found. The electron ionization mass spectra, proton nuclear magnetic resonance spectra and some electronic parameters calculated by the complete neglect of differential overlap/spectroscopy (CNDO/S) method were determined for the n-alkyl carbamates and some interesting correlations were noted. The length of the n-alkyl side chain was found to be proportional to the negative logarithm of the mass peak at m/e 44. This peak was shown to be due to the fragment O=C=N[+]H[2] and it is suggested that this correlation is due to the increasing alkyl inductive effect making the breaking of the ester bond more energetically unfavourable. There was a strong downfield shift of the NH[2] and C[alpha] methylene protons in the NMR spectra of these carbamates. The mechanism of this shift is a deshielding of the nuclei of the protons, which was predicted by the electronic charge density CNDO/S calculations. Finally, a model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential feature of this hypothesis is that carbamate is thought not to be in equilibrium between the peripheral and central compartments and that hydrolytic metabolism is the exclusive concern of the peripheral compartment, and oxidative metabolism to urinary metabolites exclusively that of the central compartment.