PHAR 4634 - Chapter 17 Page 3

Phase II

Conjugation

Conjugation reactions involve the addition of molecules naturally present in the body to the drug molecule. The drug may have undergone a phase I reaction.

Glucuronidation

This is the main conjugation reaction in the body. This occurs in the liver. Natural substrates are bilirubin and thyroxine. Aliphatic alcohols and phenols are commonly conjugated with glucuronide. Thus hydroxylated metabolites can also be conjugated. for example morphine

Acylation

Acylation, especially acetylation with the acetyl group, e.g. sulfonamides

Glycine

Glycine addition (NH₂CH₂COOH) for example nicotinic acid

Sulfate

Sulfate (-SO₄) for example morphine, paracetamol

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In most cases the metabolite is formed by production of a more polar group, for example C-H -> C-OH, or addition of a polar group, for example acetyl (CH₃COO-). Generally the resultant metabolite is more water soluble, and certainly less lipid soluble. Less drug is reabsorbed from the kidney.

Occasionally the metabolite is less water soluble. A significant example is the acetyl metabolite of some of the sulfonamides. Some of the earlier sulfonamides are acetylated to relatively insoluble metabolites which precipitated in urine, crystalluria. The earlier answer this was the triple sulfa combination, now the more commonly used sulfonamides have different elimination and solubility properties and exhibit less problems.

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In most cases the metabolites are inactive, however, occasionally the metabolite is also active, even to the extent that the metabolite may be the preferred compound to be administered. The original drug may take on the role of a pro-drug. For example:-

amitriptyline ---> nortriptyline

codeine ---> morphine

primidone ---> phenobarbital

Drug metabolism can be quantitatively altered by drug interactions. This alteration can be an increase by induction of enzyme activity or a reduction by competitive inhibition.

Induction

A large number of drugs can cause an increase over time in liver enzyme activity. This in turn can increase the metabolic rate of the same or other drugs. Phenobarbitone will induce the metabolism of itself, phenytoin, warfarin, etc. Cigarette smoking can cause increased elimination of theophylline and other compounds. Dosing rates may need to be increased to maintain effective plasma concentrations.

Inhibition

Alternately some drugs can inhibit the metabolism of other drugs. Drug metabolism being an enzymatic process can be subjected to competitive inhibition. For example, warfarin inhibits tolbutamide elimination which can lead to the accumulation of drug and may require a downward adjustment of dose.

This page was last modified: 12 February 2001