Br. J. clin. Pharmac. (1979), 8, 349-352
THE EFFECT OF SPONTANEOUS CHANGES IN URINARY pH ON MEXILETINE PLASMA CONCENTRATIONS AND EXCRETION DURING CHRONIC ADMINISTRATION TO HEALTHY VOLUNTEERS A. JOHNSTON, C.D. BURGESS, S.J. WARRINGTON, JANE WADSWORTH* & N.A.J. HAM ER Department of Clinical Pharmacology and Department of Medical Electronics, St Bartholomew's Hospital, London EClA 7BE
1 The effect of spontaneous changes in urinary pH on renal excretion and plasma concentration of mexiletine has been examined during chronic administration of subtherapeutic doses of the drug to healthy volunteers. 2 Significant correlations were found between urinary pH and the plasma concentration and renal excretion of mexiletine. 3 Prediction of plasma mexiletine concentrations from our data suggests that the amount of mexiletine in plasma would increase by more than 50% following a rise in urinary pH similar to that' which occurred spontaneously in our subjects. 4 Factors which influence urinary pH should be considered when the dosage of mexiletine is chosen. Extremes of urinary pH may account for some cases of inefficacy of the drug, and for the occurrence of unwanted effects at conventional doses.
Introduction
Methods
The effectiveness of mexiletine as an antiarrhythmic agent is well established, but its clinical use is complicated by a high incidence of undesirable effects in patients receiving the drug. These adverse effects increase in frequency and severity as the plasma drug concentration rises (Campbell, Kelly, Adgey & Shanks, 1978). Campbell et al. (1978) found only a weak correlation between plasma mexiletine level and dose, which suggests a large individual variation in patients' handling of the drug. Changes in urinary pH were reported by Kaye, Kiddie & Turner (1976) as a major cause of variation in mexiletine elimination, but Prescott, Pottage & Clements (1976) suggested that this mechanism was unlikely to have significant effects within the physiological range of urinary pH. In this study we have examined the effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration of subtherapeutic doses to healthy volunteers, to mimic the situation of patients receiving prophylactic mexiletine to control arrhythmias while leading a normal life.
Six healthy volunteers, three male and three female aged between 20 and 30 years and weighing from 57 to 78 kg, gave their informed consent to participate in the study. No subject showed any evidence of cardiac, renal or hepatic disease and none had taken any drug for at least 1 week prior to the study. Each person received a loading dose of 400 mg mexiletine hydrochloride (Mexitilg capsules) orally and thereafter 150 mg at 16.00, 00.00 and 07.00 h each day for 5 days. Each day 10 ml blood samples were drawn at 4, 6 and 8 h after the 07.00 dose (0 h). All urine was collected from 3 to 5, 5 to 7 and 7 to 9 h. The urine volume was recorded and the pH of each sample measured, within 5 min of micturition, using a pH meter (MSE-Orion). The plasma and urine specimens were stored at -20°C for later analysis. Mexiletine concentrations were estimated by a specific gas chromatographic method. The accuracy and reproducibility of this technique was checked by repeated analysis of a pool of spiked samples. Each subject's plasma and urine samples were measured in separate analytical runs together with at least 6 of these spiked replicates.
0306-5251/79/100349-04 $01.00
.)Macmillan Joumals Ltd.
A. JOHNSTON, C.D. BURGESS, S.J. WARRINGTON, JANE WADSWORTH & N.A.J. HAMER
350
Mexiletine renal clearance was calculated using the formula: Clr_amount of drug excreted/min plasma concentration of drug at midpoint of urine collection. Multiple regression analysis was used to evaluate the influence of various factors on the plasma concentration of mexiletine. Table 1 The coefficient of variation of the repeated analysis of replicate plasma and urine samples.The range and mean is given for the within assay results (n=6)
Coefficient of variation Within assay Between assays
Plasma
Urine
3.2-10.6 (6.5) 9.6
3.2-11.2 (7,3) 11.4
Table 2 Mean and range of each volunteer's urinary pH recorded during the study
Subject
Mean urinary pH
Range of urinary pH
1 2 3 4 5 6
5.59 5.42 5.92 5.69 6.93 5.53
5.14-6.24 5.12-6.42 5.33-7.85 5.10-6.58 6.40-7.86 5.04-7.35
Results
Repeated analysis of samples spiked with mexiletine 250 ng ml-' in plasma and 20 jg ml-' in urine gave mean and s.d. of 250+24 ng ml-1 (n=36) and 19.98+2.28 jg ml-' (n=38), respectively. The coefficient of variation was generally better within assays than between them (Table 1). The mean urinary pH, calculated by averaging the hydrogen ion concentrations, was 5.71 and ranged between 5.04 and 7.86 units. The pH range and mean for each subject is presented in Table 2. The following variables were used in the multiple regression analysis: urine volume, urine pH, urinary mexiletine excretion, mexiletine plasma concentration, mexiletine renal clearance, sample time and day of study. Where necessary the variables were logarithmically transformed to normalize their distribution. The multiple regression analysis was carried out for the data from all five days and separately for days 3 to 5 to exclude the influence of the loading dose from the calculations. The correlation coefficients between pairs of these variables are tabulated in Tables 3 and 4. The regression equation for ln plasma mexiletine concentrations versus 1n urinary pH is;log plasma concentration = 1. l84logpH + 2.1 (Equation 1).
Table 3 Correlation coefficients (r values) from the multiple regression analysis of the variables listed for days 1 to 5. ('P
THE EFFECT OF SPONTANEOUS CHANGES IN URINARY pH ON MEXILETINE PLASMA CONCENTRATIONS AND EXCRETION DURING CHRONIC ADMINISTRATION TO HEALTHY VOLUNTEERS A. JOHNSTON, C.D. BURGESS, S.J. WARRINGTON, JANE WADSWORTH* & N.A.J. HAM ER Department of Clinical Pharmacology and Department of Medical Electronics, St Bartholomew's Hospital, London EClA 7BE
1 The effect of spontaneous changes in urinary pH on renal excretion and plasma concentration of mexiletine has been examined during chronic administration of subtherapeutic doses of the drug to healthy volunteers. 2 Significant correlations were found between urinary pH and the plasma concentration and renal excretion of mexiletine. 3 Prediction of plasma mexiletine concentrations from our data suggests that the amount of mexiletine in plasma would increase by more than 50% following a rise in urinary pH similar to that' which occurred spontaneously in our subjects. 4 Factors which influence urinary pH should be considered when the dosage of mexiletine is chosen. Extremes of urinary pH may account for some cases of inefficacy of the drug, and for the occurrence of unwanted effects at conventional doses.
Introduction
Methods
The effectiveness of mexiletine as an antiarrhythmic agent is well established, but its clinical use is complicated by a high incidence of undesirable effects in patients receiving the drug. These adverse effects increase in frequency and severity as the plasma drug concentration rises (Campbell, Kelly, Adgey & Shanks, 1978). Campbell et al. (1978) found only a weak correlation between plasma mexiletine level and dose, which suggests a large individual variation in patients' handling of the drug. Changes in urinary pH were reported by Kaye, Kiddie & Turner (1976) as a major cause of variation in mexiletine elimination, but Prescott, Pottage & Clements (1976) suggested that this mechanism was unlikely to have significant effects within the physiological range of urinary pH. In this study we have examined the effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration of subtherapeutic doses to healthy volunteers, to mimic the situation of patients receiving prophylactic mexiletine to control arrhythmias while leading a normal life.
Six healthy volunteers, three male and three female aged between 20 and 30 years and weighing from 57 to 78 kg, gave their informed consent to participate in the study. No subject showed any evidence of cardiac, renal or hepatic disease and none had taken any drug for at least 1 week prior to the study. Each person received a loading dose of 400 mg mexiletine hydrochloride (Mexitilg capsules) orally and thereafter 150 mg at 16.00, 00.00 and 07.00 h each day for 5 days. Each day 10 ml blood samples were drawn at 4, 6 and 8 h after the 07.00 dose (0 h). All urine was collected from 3 to 5, 5 to 7 and 7 to 9 h. The urine volume was recorded and the pH of each sample measured, within 5 min of micturition, using a pH meter (MSE-Orion). The plasma and urine specimens were stored at -20°C for later analysis. Mexiletine concentrations were estimated by a specific gas chromatographic method. The accuracy and reproducibility of this technique was checked by repeated analysis of a pool of spiked samples. Each subject's plasma and urine samples were measured in separate analytical runs together with at least 6 of these spiked replicates.
0306-5251/79/100349-04 $01.00
.)Macmillan Joumals Ltd.
A. JOHNSTON, C.D. BURGESS, S.J. WARRINGTON, JANE WADSWORTH & N.A.J. HAMER
350
Mexiletine renal clearance was calculated using the formula: Clr_amount of drug excreted/min plasma concentration of drug at midpoint of urine collection. Multiple regression analysis was used to evaluate the influence of various factors on the plasma concentration of mexiletine. Table 1 The coefficient of variation of the repeated analysis of replicate plasma and urine samples.The range and mean is given for the within assay results (n=6)
Coefficient of variation Within assay Between assays
Plasma
Urine
3.2-10.6 (6.5) 9.6
3.2-11.2 (7,3) 11.4
Table 2 Mean and range of each volunteer's urinary pH recorded during the study
Subject
Mean urinary pH
Range of urinary pH
1 2 3 4 5 6
5.59 5.42 5.92 5.69 6.93 5.53
5.14-6.24 5.12-6.42 5.33-7.85 5.10-6.58 6.40-7.86 5.04-7.35
Results
Repeated analysis of samples spiked with mexiletine 250 ng ml-' in plasma and 20 jg ml-' in urine gave mean and s.d. of 250+24 ng ml-1 (n=36) and 19.98+2.28 jg ml-' (n=38), respectively. The coefficient of variation was generally better within assays than between them (Table 1). The mean urinary pH, calculated by averaging the hydrogen ion concentrations, was 5.71 and ranged between 5.04 and 7.86 units. The pH range and mean for each subject is presented in Table 2. The following variables were used in the multiple regression analysis: urine volume, urine pH, urinary mexiletine excretion, mexiletine plasma concentration, mexiletine renal clearance, sample time and day of study. Where necessary the variables were logarithmically transformed to normalize their distribution. The multiple regression analysis was carried out for the data from all five days and separately for days 3 to 5 to exclude the influence of the loading dose from the calculations. The correlation coefficients between pairs of these variables are tabulated in Tables 3 and 4. The regression equation for ln plasma mexiletine concentrations versus 1n urinary pH is;log plasma concentration = 1. l84logpH + 2.1 (Equation 1).
Table 3 Correlation coefficients (r values) from the multiple regression analysis of the variables listed for days 1 to 5. ('P
