Location and Function of OCTN2
OCTN2, commonly known as the carnitine /organic cation transporter 2, mediates both sodium dependent and independent transport. Although OCTN2 is expressed ubiquitously, its presence on the apical membrane of proximal tubules in the kidney is especially important due to its role in the renal tubular reabsorption of L-carnitine. L-Carnitine is derived from the diet and well as being produced endogenously. It is important in the transport of long chain fatty acids from the cytosol into mitochondria and the subsequent energy production by ß-oxidation. The OCTN2 transporter is clinically relevant because deficiency of the OCTN2 gene in humans causes systemic carnitine deficiency (SCD). This deficiency is characterised by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia as well as being linked to sudden infant death syndrome. Mutations in OCTN2 have also been associated with Crohn’s disease susceptibility.
Several drugs are known to inhibit OCTN2. These include valproic acid, emetine and pivalic acid as well as several ß-lactam antibiotics such as cephaloridine, cefoselis, cefipime and cefluprenam. It has been proposed that inhibition of OCTN2 could potentially lead to secondary carnitine deficiency. Indeed, carnitine deficiency has been observed in patients prescribed valproic acid as an anti-epilepsy treatment with the adverse effects observed being symptomatic of this deficiency. Furthermore, carnitine clearly has an important function in mitochondrial function and energy production, therefore, it is possible that patients with an underlying mitochondrial dysfunction may be more susceptible to adverse effects of carnitine deficiency through OCTN2 inhibition.
Despite the clear association between valproic acid toxicity and carnitine deficiency, the clinical evidence linking OCTN2 inhibition to drug-induced toxicity has, in many cases, been difficult to establish and, as such, the FDA and EMA do not currently include OCTN2 in the recommended panel of transporter assays for regulatory drug interaction studies. Time will tell if this situation will change as our knowledge of the OCTN2 transporter grows and further clinical evidence is established.