Effect of drugs on the formation of smooth endoplasmic reticulum and drug-metabolizing enzymes.

An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.

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Warfarin STEREOCHEMICAL ASPECTS OF ITS METABOLISM AND THE INTERACTION WITH PHENYLBUTAZONE

It is evident that metabolic interactions can occur among drugs, insecticides, food additives, carcinogenic hydrocarbons, and a variety of environmental chemicals. A common denominator governing these effects is the versatile nature of the liver microsomal enzymes that metabolize chemicals with diverse structures and biological activities, and the fact that these enzymes can be stimulated or inhibited by other chemicals administered simultaneously. The discovery of these particular enzymes in the 1950's laid the groundwork for the current research on metabolic interactions. Such research provides information that is helpful in the evaluation of the safety and efficacy of drugs and environmental chemicals, and suggests new directions for further research. Some examples are as follows.

Metabolic interactions among environmental chemicals and drugs.

Chronic treatment of experimental animals with phenobarbital resulted in accelerated metabolism of a variety of drugs such as bishydroxycoumarin, diphenylhydantoin, and antipyrine. Evidence for the ability of drugs to stimulate drug metabolism in man has come from the results of studies presented here, showing that phenobarbital decreases the plasma level of diphenylhydantoin and bishydroxycoumarin. The decreased plasma leGel of bishydroxycoumarin in man was correlated with a decreased anticoagulant action of the drug. The ability of a drug to stimulate its own metabolism or the metabolism of another drug appears to have important implications in clinical pharmacologic studies, as weU as to the problem of drug therapy in man.

W. Chen

Papers

Accelerated aminopyrine metabolism in human subjects pretreated with phenylbutazone

A study of structure-activity relationships in regard to species difference in the phenylbutazone series