Objectives: To study the effect of the different ORM1 phenotypes on plasma free drug
concentration and plasma protein
binding of
amitriptyline. Methods: Twenty eight healthy volunteers with thre e ORM1 phenotypes containing homozygotes ORM1 F1( n =10) and ORM1 S( n =8), and heteroz ygote ORM1 F1S( n =10) identified by isoelectri c focusing on polyacrylamide gels following by immunoblotting after desialylation of sera were selected. After a single 5 0 mg of amitriptyline hydrochloride per os, plasma total and free(in ultrafiltrate) concentrations were determined and the pharmacokinetic parameters and the binding percentage in sera of the drug were calculated. Results: Plasma levels of OR M and albumin proteins were similar in the three groups( P >0.05). The elimination t 1/2 values and the other pharmacokineti cs parameters of amitriptyline did not be affected by the different ORM1 phenotypes. Free amitriptyline
concentration i n ORM1 F1 phenotype subjects was significant higher than that in ORM1 S phe notype( P <0.01), but percentage of the plasma protein binding after dosing for the subjects with ORM1 F1 phenotype, (82. 77±4.05)% at 12 h, (79.99±4.39)% at 24 h was lower than that with ORM1 S phenotype( P <0.01). Conclusions: The different ORM1 phenotypes may affect the dispositi on of amitriptyline in the subjects. T he functional heterogeneity of ORM1 could be responsible for the differences in plasma protein binding of amitriptyline. Therefore, monitoring of the free amitriptyli ne concentration would be important for the patients with different ORM1 phenotypes when amitriptyline treatment.