Mexiletine disposition: individual variation in response to urine acidification and alkalinisation

The disposition of mexiletine has been studied in five subjects on two occasions with urine pH controlled at 5.0 and at 8.0. With acid urine total plasma clearance was similar in all subjects (462 to 497 ml min-1) and the plasma half-life ranged from 3.8 to 9.2 h (mean 6.7 h). With alkaline urine the total plasma clearance varied considerably (239 to 441 ml min-1); the mean half-life, 9.7 h, (range 7.6 to 12.7 h) was not significantly different from that in the acid urine study. Renal clearance fell greatly in every subject on alkalinisation of the urine. The total plasma clearance fell by a similar amount in two. In the remaining three the fall in total clearance was much smaller because of an increase in non-renal clearance. The reduction in total plasma clearance only just achieved statistical significance. The increase in predicted steady-state plasma mexiletine concentrations during infusion with change in urine pH from 5 to 8 varied between +5% and +95% (mean +39%). Changes in urine pH have a predictable effect upon renal clearance of mexiletine. However, disposition is changed in an unpredictable manner and inter-subject variation in distribution volume and non-renal clearance are important factors.