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Letters to the Editor
Editor, – Tailoring treatment to the individual is the art of therapeutics and is supported by an increasing understanding of inter-and intra-individual variability (the science). Dose adjustment in liver impairment is difficult because a reliable predictor of hepatic drug clearance is lacking.1 Drs Sloss and Kubler recently discussed the use of the Child-Pugh classification to guide dose adjustment in liver impairment (Aust Prescr 2009;32:32-5). This is a tool of last resort and there are several other factors that can and should be used to guide dosing.
If measures of clinical effects (desired and adverse) are available, these can be used to guide dosing. Firstly, many drugs have validated biomarkers of drug effect (for example INR for warfarin) or surrogate markers of clinical outcome (for example HIV viral load for antiretroviral treatment).2 Similarly many drugs have concentration-related symptoms, for example pain for analgesics, or dry mouth and constipation for anticholinergics. Secondly, the concentration of some drugs can be easily measured. This is particularly valuable as therapeutic drug monitoring is available for many drugs with narrow therapeutic ranges, the drugs that prescribers are most concerned about in hepatic impairment. Immunosuppressants and anticonvulsants are examples of these.
We also recommend that prescribers consider the potential effect of liver impairment on the active drug moiety by changes in clearance (potentially decreased) and oral bioavailability (potentially increased). Pharmacokinetic variability due to hepatic impairment can be managed by considering clearance of the active moiety and first-pass metabolism in conjunction with monitoring drug effects, biomarkers, or concentrations.
Flinders Medical Centre and Flinders University, SA
Royal Brisbane and Women's Hospital and The University of Queensland
Professor of Clinical Pharmacology
Flinders University, SA
Professor of Clinical Pharmacology
University of Adelaide, SA
Editor, – Drs Sloss and Kubler discuss hepatic metabolism in a recent article (Aust Prescr 2009;32:32-5). They point out that, in phase I reactions, hydrolysis is very common. They go on to state that hydrolysis involves the addition of molecular oxygen. This sounds more like oxidation.
The term 'hydrolysis' refers to water and involves cleavage of a molecule with the addition of water, whether it is mediated by acid or base or by a hydrolase enzyme. Hydrolases are, in fact, like a particular type of transferase enzyme where water accepts the transferred group. So water is actually utilised and not created as stated in the article.
In the example given, acetylsalicylic acid (aspirin) reacts with water to form acetate (acetic acid) and the free phenolic salicylate, salicylic acid.
The aqueous nature of the body makes hydrolysis very probable. In fact, it is by confining easily hydrolysed intermediates within a hydrophobic enzyme active site that unique reactions can occur enzymatically that would be impossible in aqueous solution.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
- Twaddell S. Surrogate outcome markers in research and clinical practice. Aust Prescr 2009;32:47-50.