Robert K. Griffith

The Hepatic First‐Pass Metabolism of Problematic Drugs

The first‐pass hepatic metabolism of a number of important therapeutic agents is inconsistent with traditional models that assume that the hepatic extraction ratio of a drug is constant in each individual (independent of the concentration of drug in the hepatic sinusoidal blood and also independent of the history of exposure to the drug). In this review, the authors examine the first‐pass metabolism of five “problematic drugs” (propranolol, lidocaine, propafenone, verapamil, and nitroglycerin). Each of these compounds has unique facets to its hepatic clearance and pharmacokinetics as well as striking similarities. Selected aspects of first‐pass metabolism are reviewed, and a theory that may explain some of the unusual behavior of the four lipophilic bases (propranolol, lidocaine, propafenone, and verapamil) is presented. Finally, the unusual and variable clearance of nitroglycerin is discussed.

Improved Syntheses of Vinyl Imidazoles1

Abstract A series of vinylimidazoles were synthesized via Wittig reactions on N-tritylimidazole-4-carboxaldehyde. Activated phosphonate ylids afforded yields in excess of 90% while the yields from unactivated ylids ranged from 10–82%. The trityl group may be removed by mild acid hydrolysis in high yield.

Multisubstrate analogue inhibitors of glucosamine-6-phosphate synthase from Candida albicans.

Compounds 1-6 were designed as multisubstrate inhibitors of glucosamine synthase. These compounds are also useful probes for measuring the distances between the two active sites in the multidomain protein. Our data suggest that the two binding pockets are in close proximity to each other.

Histamine receptor activation by unsaturated (allyl and propargyl) homologs of histamine

The spectrum of agonist activity for three new homologs of histamine (cis- and trans-imidazolylallylamine and imidazolylpropargylamine) was evaluated in the isolated guinea pig ileum and right atrium. The homologs were about three log units less potent than histamine in stimulating contractions of the longitudinal muscles of the ileum, but they were histamine-like, pharmacologically, because they were sensitive to blockade by pyrilamine and resistant to blockade by atropine. In the right atrium, these weak agonists were partially sensitive to blockade by cimetidine. The agonist activity of the cis-isomer in particular was completely blocked by a combination of cimetidine and propranolol, but resistant to reserpine treatment (neuronal catecholamine depletion). Therefore, these homologs of histamine have the ability to stimulate H1- and H2-histamine receptors andbeta-adrenoreceptorsin vitro.

Synthesis of 4(5)-imidazolyl allylamines and propargylamines as inhibitors of diamine oxidase

Abstract A series of four side-chain unsaturated histamine analogs were synthesized and evaluated as inhibitors of Diamine Oxidase, (DAO). All four target compounds were potent competitive inhibitors of DAO with Ki values ranging from 0.17 to 7.1 μM.