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.
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.
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.
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.
Copyright 2001 David W.A. Bourne