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The renal clearances of nicotine and cotinine, its proximate metabolite, vary considerably between individuals. This twin study looked at the influences of genetic and environmental factors on renal clearance.
One hundred and ten monozygotic and 29 dizygotic healthy twin pairs with a mean age of 37.7 years were recruited. The group was predominantly female (69.9%) and Caucasian (76.1%). An intravenous infusion of deuterium-labelled nicotine and cotinine was administered after an overnight fast. In smokers, the dose was dependent upon their plasma cotinine concentration. Blood samples were taken at intervals and urine was collected over 8 h. These compounds demonstrate minimal protein binding, so their glomerular filtration was estimated by the glomerular filtration rate (GFR).
Analysis using twin methods revealed the presence of non-additive genetic effects on GFR and net secretory/reabsorptive clearance. Additive genetic effects seemed to be more important in the renal clearance of cotinine. The study was not powered sufficiently to allow biometric models to separate additive genetic effects from non-additive genetic effects and shared environmental factors.
Renal clearance comprises passive glomerular filtration/reabsorption, previously shown to be largely under environmental control, and active secretion which has been found to be heritable. This study showed that, at uncontrolled urine pH, there was net reabsorption of both compounds in most subjects. Therefore, there may be an overriding genetically-controlled active secretory process despite net reabsorption or, in this case, reabsorption may be genetically influenced. Furthermore, the results suggest that nicotine and cotinine are cleared in slightly different ways and are likely to be influenced by different factors.
Future studies to determine the factors influencing renal drug clearance may make it possible to individualise drug prescribing, increasing effectiveness and safety.
▸ Benowitz NL, Lessov-Schlaggar CN, et al. Genetic influences in the variation in renal clearance of nicotine and cotinine. Clin Pharmacol Ther 2008;84:243–7.
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