CARDIOVASCULAR
Effect Pharmacokinetics Francis
Y. W.
Donald
of Probenecid on the and Pharmacodynamics of Procainamide Lam,
PharmD,
Chang,
Rebecca
PharmD,
and
A. Boyd,
Kathleen
PhD,
Shu
M. Giacomini,
K. Chin,
BS,
PhD
tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 ± 95 mL/min without probenecid vs. 478 ± 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed. Renal
R esults
from several in vitro and in vivo studies’-9 appear to contradict the general assumption that there is no interaction between organic anions and cations in the renal proximal tubule. Probenecid, the classic inhibitor of renal organic anion transport, has been shown to inhibit the transport of the organic cations cimetidine,5 tetraethylammonium chloride (TEA),3 and N1 -methylnicotinamide (NMN)6 in various in vitro renal tissue preparations. Administration of probenecid to rats prolonged the half-life7 and decreased the renal clearance8 of cimetidine. In humans, the renal clearance of cimetidine9 and fa-
From the Department of Pharmacology Health Science Center at San Antonio, macy
(Drs.
Boyd,
Chin,
and
Giacomini)
(Dr. Lam), University and the Department and
Division
of Texas of Phar-
of Clinical
Phar-
(Dr. Chang), University of California, San Francisco California. This work was supported in part by National Institutes of Health Grants GM 26691 and GM36780. Address for reprints: Y.W. Francis Lam, PharmD, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7765. macy
J ClIn Pharmacol
1991;31:429-432
motidine1#{176} was reduced after oral administration of probenecid. Although these interactions are not clinically relevant to the therapeutic use of these two compounds because of their large therapeutic indexes, the studies demonstrated that renal interactions between organic cations and organic anions can occur in humans. This investigation extended these studies and assessed clinical relevance by determining if a similar interaction between probenecid and the organic cation, procainamide, occurs in humans and if so, whether such an interaction alters the pharmacodynamics of procainamide. Procainamide is an antiarrhythmic agent with a narrow range of therapeutic plasma concentrations. Renal excretion is an important route of elimination for procainamide and proximal tubular secretion plays a significant part in its elimination by the kidney.11”2 Hence, any significant interaction between probenecid and procainamide could have implications for the clinical use of these compounds. Results from in vitro inhibition studies”5 and reports of a drug interaction between cimetidine and procainamide in humans’315 suggest that cimetidine and procainamide share the same organic
429
LAM ET AL
cation transport that probenecid of procainamide.
system. could
It therefore seemed decrease the renal
possible clearance
Protocol
This study was approved by the Committee on Human Research, University of California, San Francisco, and carried out in the Drug Studies Unit in the Department of Pharmacy at the University of California, San Francisco. Six healthy adult male volunteers between the ages of 24 and 36, and weighing between 62.3 and 82 kg, were recruited. Informed consent was obtained before each subject was enrolled into the study. All subjects were determined to be in good health by physical examinations, blood chemistries (SMA25), complete blood counts and differentials, ECGs, and urinalyses. A randomized, two-treatment period (A and B), crossover design was used in this clinical study, with a 7-day washout period between treatments. In period A, a 750-mg dose of procainamide hydrochloride was infused over 60 minutes. In period B, a 2-g oral dose of probenecid was administered to each subject 2 hours before the administration of procainamide. In each period, 10 mL of blood was collected from all subjects immediately before and at 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 24 hours after the start of the procainamide infusion. Plasma was harvested and frozen in glass vials at -20#{176}Cuntil assayed. Urine samples were collected before the procainamide dose, and during the intervals of 0-1, 1-2, 2-4, 4-6, 6-8, 8-12, 12-24, and 24-48 hours after the start of the procainamide infusion. The pH and volume of each urine sample were measured immediately on collection, and a 20mL aliquot was frozen at -20#{176}Cuntil assayed. Supine blood pressures, heart rates, and ECGs were recorded before, and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours after the start of the procainamide infusion. QT intervals were measured and normalized for heart rate (QTJ according to a nomogram that was constructed using Bazett’s formula.’6 Procainamide
Assay
Concentrations of procainamide in plasma and urine were determined by a homogeneous enzyme immunoassay procedure (EMIT#{174}Procainamide Assay, Syva Co., Palo Alto, CA). Calibration curves were prepared over the concentration range of 0.25 g/mL to 8.0 ig/mL for analysis of plasma samples and 1.0 to 16 ig/mL for analysis of urine samples. For each
430
or urine samples A and B were
Pharmacokinetic
METHODS Experimental
subject, plasma ment periods same day.
#{149} .1 ClIn Pharmacol
1991;31:429-432
from both treatanalyzed on the
Analysis
In each subject, plasma concentration-time curves were fit to a two-compartment model using the DRUGFUN program on the PROPHET system.’7 The terminal elimination half-life (tl/2) of procainamide was calculated from the terminal elimination rate constant (lj, obtained from the computer fit, as 0.693/li. The area under the plasma concentration vs. time curve from time zero to infinity (AUCcXD) of procainamide was estimated by the linear trapezoidal rule for increasing concentrations and by the logarithmic trapezoidal rule for declining concentrations, with extrapolation to infinity. The plasma clearance (CL) of procainamide was calculated as dose/AUCco. The steady-state volume of distribution (V9J was calculated as (dose) (AUMC)/(AUCco)’, where AUMC is the area under the first moment of the plasma concentration-time curve. A correction was made for the time of infusion by subtracting [(t/ 2) X (Dose/AUC)] from the V values, where t is the duration of the infusion. Renal clearance (CLr) of procainamide was calculated as A8co/AUCco, where A8co is the amount of unchanged procainamide excreted in the urine in 24 hours, a good approximation of the total amount excreted. Fractional CLr for each urine collection period were determined as Ae (t1-t,)/AUC(t1-t2), where Ae(t1-t2) is the amount of unchanged procainamide excreted in urine in a collection period and AUC(t,t,) is the area under the plasma concentration-time curve during the same interval. Nonrenal clearance (CL) of procainamide was calculated as CL CLr. -
Statistical
Analysis
Results are presented as the mean ± SD of the data that was obtained from six subjects except where otherwise noted. Statistical evaluation of differences in mean pharmacokinetic parameters between treatment periods was carried out by the Student’s paired test. The relationship between change in QTc interval and plasma procainamide concentration was evaluated by linear least-squares regression analysis. For both statistical tests, P
Effect Pharmacokinetics Francis
Y. W.
Donald
of Probenecid on the and Pharmacodynamics of Procainamide Lam,
PharmD,
Chang,
Rebecca
PharmD,
and
A. Boyd,
Kathleen
PhD,
Shu
M. Giacomini,
K. Chin,
BS,
PhD
tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 ± 95 mL/min without probenecid vs. 478 ± 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed. Renal
R esults
from several in vitro and in vivo studies’-9 appear to contradict the general assumption that there is no interaction between organic anions and cations in the renal proximal tubule. Probenecid, the classic inhibitor of renal organic anion transport, has been shown to inhibit the transport of the organic cations cimetidine,5 tetraethylammonium chloride (TEA),3 and N1 -methylnicotinamide (NMN)6 in various in vitro renal tissue preparations. Administration of probenecid to rats prolonged the half-life7 and decreased the renal clearance8 of cimetidine. In humans, the renal clearance of cimetidine9 and fa-
From the Department of Pharmacology Health Science Center at San Antonio, macy
(Drs.
Boyd,
Chin,
and
Giacomini)
(Dr. Lam), University and the Department and
Division
of Texas of Phar-
of Clinical
Phar-
(Dr. Chang), University of California, San Francisco California. This work was supported in part by National Institutes of Health Grants GM 26691 and GM36780. Address for reprints: Y.W. Francis Lam, PharmD, Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7765. macy
J ClIn Pharmacol
1991;31:429-432
motidine1#{176} was reduced after oral administration of probenecid. Although these interactions are not clinically relevant to the therapeutic use of these two compounds because of their large therapeutic indexes, the studies demonstrated that renal interactions between organic cations and organic anions can occur in humans. This investigation extended these studies and assessed clinical relevance by determining if a similar interaction between probenecid and the organic cation, procainamide, occurs in humans and if so, whether such an interaction alters the pharmacodynamics of procainamide. Procainamide is an antiarrhythmic agent with a narrow range of therapeutic plasma concentrations. Renal excretion is an important route of elimination for procainamide and proximal tubular secretion plays a significant part in its elimination by the kidney.11”2 Hence, any significant interaction between probenecid and procainamide could have implications for the clinical use of these compounds. Results from in vitro inhibition studies”5 and reports of a drug interaction between cimetidine and procainamide in humans’315 suggest that cimetidine and procainamide share the same organic
429
LAM ET AL
cation transport that probenecid of procainamide.
system. could
It therefore seemed decrease the renal
possible clearance
Protocol
This study was approved by the Committee on Human Research, University of California, San Francisco, and carried out in the Drug Studies Unit in the Department of Pharmacy at the University of California, San Francisco. Six healthy adult male volunteers between the ages of 24 and 36, and weighing between 62.3 and 82 kg, were recruited. Informed consent was obtained before each subject was enrolled into the study. All subjects were determined to be in good health by physical examinations, blood chemistries (SMA25), complete blood counts and differentials, ECGs, and urinalyses. A randomized, two-treatment period (A and B), crossover design was used in this clinical study, with a 7-day washout period between treatments. In period A, a 750-mg dose of procainamide hydrochloride was infused over 60 minutes. In period B, a 2-g oral dose of probenecid was administered to each subject 2 hours before the administration of procainamide. In each period, 10 mL of blood was collected from all subjects immediately before and at 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 24 hours after the start of the procainamide infusion. Plasma was harvested and frozen in glass vials at -20#{176}Cuntil assayed. Urine samples were collected before the procainamide dose, and during the intervals of 0-1, 1-2, 2-4, 4-6, 6-8, 8-12, 12-24, and 24-48 hours after the start of the procainamide infusion. The pH and volume of each urine sample were measured immediately on collection, and a 20mL aliquot was frozen at -20#{176}Cuntil assayed. Supine blood pressures, heart rates, and ECGs were recorded before, and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours after the start of the procainamide infusion. QT intervals were measured and normalized for heart rate (QTJ according to a nomogram that was constructed using Bazett’s formula.’6 Procainamide
Assay
Concentrations of procainamide in plasma and urine were determined by a homogeneous enzyme immunoassay procedure (EMIT#{174}Procainamide Assay, Syva Co., Palo Alto, CA). Calibration curves were prepared over the concentration range of 0.25 g/mL to 8.0 ig/mL for analysis of plasma samples and 1.0 to 16 ig/mL for analysis of urine samples. For each
430
or urine samples A and B were
Pharmacokinetic
METHODS Experimental
subject, plasma ment periods same day.
#{149} .1 ClIn Pharmacol
1991;31:429-432
from both treatanalyzed on the
Analysis
In each subject, plasma concentration-time curves were fit to a two-compartment model using the DRUGFUN program on the PROPHET system.’7 The terminal elimination half-life (tl/2) of procainamide was calculated from the terminal elimination rate constant (lj, obtained from the computer fit, as 0.693/li. The area under the plasma concentration vs. time curve from time zero to infinity (AUCcXD) of procainamide was estimated by the linear trapezoidal rule for increasing concentrations and by the logarithmic trapezoidal rule for declining concentrations, with extrapolation to infinity. The plasma clearance (CL) of procainamide was calculated as dose/AUCco. The steady-state volume of distribution (V9J was calculated as (dose) (AUMC)/(AUCco)’, where AUMC is the area under the first moment of the plasma concentration-time curve. A correction was made for the time of infusion by subtracting [(t/ 2) X (Dose/AUC)] from the V values, where t is the duration of the infusion. Renal clearance (CLr) of procainamide was calculated as A8co/AUCco, where A8co is the amount of unchanged procainamide excreted in the urine in 24 hours, a good approximation of the total amount excreted. Fractional CLr for each urine collection period were determined as Ae (t1-t,)/AUC(t1-t2), where Ae(t1-t2) is the amount of unchanged procainamide excreted in urine in a collection period and AUC(t,t,) is the area under the plasma concentration-time curve during the same interval. Nonrenal clearance (CL) of procainamide was calculated as CL CLr. -
Statistical
Analysis
Results are presented as the mean ± SD of the data that was obtained from six subjects except where otherwise noted. Statistical evaluation of differences in mean pharmacokinetic parameters between treatment periods was carried out by the Student’s paired test. The relationship between change in QTc interval and plasma procainamide concentration was evaluated by linear least-squares regression analysis. For both statistical tests, P
