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London Centre for Paediatric Endocrinology University College London London W1N 8AA, United Kingdom
To the editor:
The paper entitled "Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning" by Plat et al. (1) was of great interest to me, and the authors’ findings are extremely important. I would like to comment, however, on the hydrocortisone clearance (CL) findings and the method of its estimation.
In their study, the authors define hydrocortisone CL as "the time required to achieve a 50% reduction from the maximum difference in plasma cortisol levels between the hydrocortisone and placebo conditions," and they find hydrocortisone CL to be 50% slower in the evening than in the morning (156 ± 15 min vs. 109 ± 13 min, P < 0.003; page 3087, paragraph 5).
CL describes the efficiency of irreversible elimination of a drug from the body. It is actually defined as "the volume of blood cleared of the drug per unit time," and the units are, thus, volume per time, usually liters per hour (L/h) or milliliters per minute (mL/min). Another definition of CL is that it is the constant relating the concentration of the drug in the plasma to the elimination rate:
Elimination rate (mg/h) = CL (L/h) * plasma drug concentration (mg/L)
It is apparent that for a given CL the elimination rate varies directly with the plasma drug concentration (2).
The best method of calculating CL is to give a single iv dose of the drug (to ensure 100% bioavailability of the drug) and draw frequent blood samples for measurement of the plasma drug concentrations until they reach undetectable levels. Then CL can be calculated by dividing the dose administered iv by the area under the drug concentration vs. time curve (AUC) from time = 0 min to infinite time (2, 3, 4):
CL (L/h)=dose (iv) (mg)/AUC0–inf (mg * h/L)
Alternatively, when the volume of distribution (V) and half-life (t1/2) of a drug have been estimated, CL can be calculated using the formula:
t1/2 = 0.693 * V/CL,
where 0.693 is the natural log of 2 (3, 5).
Based on the above principles of pharmacokinetics it becomes clear that the results that the authors obtained on the hydrocortisone CL may not be reliable, because they assumed CL to be the time required to achieve 50% reduction from the maximum difference in plasma cortisol concentrations achieved after administration of hydrocortisone and placebo.
But do they refer to hydrocortisone half-life rather than CL, hence the units are minutes and not L/h or mL/min? If this is the case, then half-life should be estimated as the time required for the plasma cortisol concentrations achieved in individual patients to fall by half. Plasma cortisol concentrations should be natural log (loge) transformed before further statistical analysis. The relationship between time and the transformed data can be described by linear regression. Then, half-life can be calculated by dividing 0.693 (loge 2) by the slope of the regression line that represents the elimination constant rate (5). Like CL, half-life is also most accurately estimated following iv administration of the drug.
I would be interested in having the authors’ views and explanation for their estimation and findings.
Received May 18, 2000.
References
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