Pharmacokinetics of Red Blood Cell Phenothiazine and Clinical Effects Acute
Dystonic Reactions
David L. Garver, MD; John M. Davis, MD; Hartoune Dekirmenjian, PhD; Frank D. Jones, MD; Regina Casper, MD; Joseph Haraszti, MD
\s=b\ Pharmacokinetics of the phenothiazine, butaperazine, were studied in relationship to acute dystonic reactions. Dystonias appeared on falling drug concentrations, more than one half-life after plasma and red blood cell (RBC) peak butaperazine concentrations. Red blood cell butaperazine kinetics differentiated better than did plasma butaperazine levels those subjects in whom dystonias would develop from those in whom they did not. We conclude that RBC phenothiazine levels may more clearly reflect drug concentration at critical brain sites than do simple plasma drug levels. Furthermore, dystonic reactions may be the result of differential sensitivity of two or more receptor systems to receptor blockade by antischizophrenic agents. (Arch Gen Psychiatry 33:862-866, 1976)
variation of clinical response following similar of phenothiazines and other antischizophrenic is well known in clinical practice. Recently, clinical pharmacologists have sought to relate such variability in clinical response to differing concentrations of drug in plasma.'" ' Plasma levels of neuroleptics have been found to provide considerable information concerning absorption and rates of metabolism of drug. But plasma levels do not reflect membrane phenomena that govern either the passage of such lipid soluble drugs across the membranes of the blood-brain barrier or the accumulation of drug by tissues, such as drug present at critical central nervous system (CNS) sites.4
Indidosages vidual agents
Accepted
for publication Feb 16, 1976. From the Illinois State Psychiatric Institute and the Department of Psychiatry, University of Chicago. Reprint requests to Illinois State Psychiatric Institute, 1601 W Taylor St, Chicago, IL 60612 (Dr Garver).
Downloaded From: by a East Carolina University User on 01/02/2019
It is possible that membrane parameters governing the passage of drug across the blood-brain barrier and its accumulation at critical CNS sites may be similar to those determining its accumulation in or on other cells, such as the peripheral red blood cell (RBC). This hypothesis can be tested functionally by relating RBC-bound phenothiazine concentrations to clinical effects of the drug. If the hypoth¬ esis is correct, clinical effects of the drug would be expected to correlate better with RBC-bound phenothia¬ zine concentrations than with plasma levels of drug. Clinically, the most dramatic of the CNS effects of neuroleptic drugs are the acute dystonic reactions such as torticollis, retrocollis, opisthotomus, and oculogyrus. Here¬ in we relate the course of occurrence of such dystonic reactions to single-dose pharmacokinetic parameters of a phenothiazine. Such pharmacokinetic parameters of both plasma and RBC-bound butaperazine, a potent antischizo¬ phrenic phenothiazine of the piperazine group, are reported in dystonic and nondystonic patients. SUBJECTS AND METHODS
Schizophrenic patients, who consented to multiple blood draw¬ ings during their course of drug treatment with butaperazine, began their treatment with a single 40-mg orally administered dose of the drug. Chronic administration of butaperazine began 72 hours later. As it became apparent that such an initial single dose produced a high incidence of dystonic reactions, patients were informed of such possible side effects together with reassurance that such reactions would be readily reversed by additional medication, should the reactions appear. Blood samples were collected routinely in edetate sodium at 0, 2, 4, 8, 15, 36, 45, and 72 hours after the initial
40-mg dose. Plasma and RBCs
immediately separated. Both plasma and RBC extract fluorometrically assayed according to the method of Davis
were were
et als
Kinetics of Plasma and Red Blood Cell Time of
Butaperazine in Subjects Who Develop Dystonias and
Subjects Who Did Not*
Area Beneath Buta¬
Butaper¬ azine, ng/ml
Peak
Dystonie
in
/3-Half-Life, hr
perazine Curve, ¿tg/hr
After Buta¬ perazine, hr
Plasma
RBC
Plasma
RBC
Plasma
RBC
23 25 26 27 27 27 28 56 29.9 ±3.8
70 320 345 260 690 310 120 119 279 ± 70
18 520 144 71 42 90 215 50 144 ±58
8.4 6.3 9.2 26.6 16.0 9.0 11.5 12.1 12.4 ±2.3
...t
0.69 3.39 4.60 4.28 15.67 2.46 4.15 1.29 4.57 ±1.7
0.07 4.20 1.90 2.10 1.15 3.60 1.26 1.16 1.93 ±.50
103 130 90 600 420 269 ±103
42 40 10 127 30 50 ±20
NS
NS
9.8 8.3 5.7 8.5 5.6 7.6 ±0.8
Dystonic Reactions
David L. Garver, MD; John M. Davis, MD; Hartoune Dekirmenjian, PhD; Frank D. Jones, MD; Regina Casper, MD; Joseph Haraszti, MD
\s=b\ Pharmacokinetics of the phenothiazine, butaperazine, were studied in relationship to acute dystonic reactions. Dystonias appeared on falling drug concentrations, more than one half-life after plasma and red blood cell (RBC) peak butaperazine concentrations. Red blood cell butaperazine kinetics differentiated better than did plasma butaperazine levels those subjects in whom dystonias would develop from those in whom they did not. We conclude that RBC phenothiazine levels may more clearly reflect drug concentration at critical brain sites than do simple plasma drug levels. Furthermore, dystonic reactions may be the result of differential sensitivity of two or more receptor systems to receptor blockade by antischizophrenic agents. (Arch Gen Psychiatry 33:862-866, 1976)
variation of clinical response following similar of phenothiazines and other antischizophrenic is well known in clinical practice. Recently, clinical pharmacologists have sought to relate such variability in clinical response to differing concentrations of drug in plasma.'" ' Plasma levels of neuroleptics have been found to provide considerable information concerning absorption and rates of metabolism of drug. But plasma levels do not reflect membrane phenomena that govern either the passage of such lipid soluble drugs across the membranes of the blood-brain barrier or the accumulation of drug by tissues, such as drug present at critical central nervous system (CNS) sites.4
Indidosages vidual agents
Accepted
for publication Feb 16, 1976. From the Illinois State Psychiatric Institute and the Department of Psychiatry, University of Chicago. Reprint requests to Illinois State Psychiatric Institute, 1601 W Taylor St, Chicago, IL 60612 (Dr Garver).
Downloaded From: by a East Carolina University User on 01/02/2019
It is possible that membrane parameters governing the passage of drug across the blood-brain barrier and its accumulation at critical CNS sites may be similar to those determining its accumulation in or on other cells, such as the peripheral red blood cell (RBC). This hypothesis can be tested functionally by relating RBC-bound phenothiazine concentrations to clinical effects of the drug. If the hypoth¬ esis is correct, clinical effects of the drug would be expected to correlate better with RBC-bound phenothia¬ zine concentrations than with plasma levels of drug. Clinically, the most dramatic of the CNS effects of neuroleptic drugs are the acute dystonic reactions such as torticollis, retrocollis, opisthotomus, and oculogyrus. Here¬ in we relate the course of occurrence of such dystonic reactions to single-dose pharmacokinetic parameters of a phenothiazine. Such pharmacokinetic parameters of both plasma and RBC-bound butaperazine, a potent antischizo¬ phrenic phenothiazine of the piperazine group, are reported in dystonic and nondystonic patients. SUBJECTS AND METHODS
Schizophrenic patients, who consented to multiple blood draw¬ ings during their course of drug treatment with butaperazine, began their treatment with a single 40-mg orally administered dose of the drug. Chronic administration of butaperazine began 72 hours later. As it became apparent that such an initial single dose produced a high incidence of dystonic reactions, patients were informed of such possible side effects together with reassurance that such reactions would be readily reversed by additional medication, should the reactions appear. Blood samples were collected routinely in edetate sodium at 0, 2, 4, 8, 15, 36, 45, and 72 hours after the initial
40-mg dose. Plasma and RBCs
immediately separated. Both plasma and RBC extract fluorometrically assayed according to the method of Davis
were were
et als
Kinetics of Plasma and Red Blood Cell Time of
Butaperazine in Subjects Who Develop Dystonias and
Subjects Who Did Not*
Area Beneath Buta¬
Butaper¬ azine, ng/ml
Peak
Dystonie
in
/3-Half-Life, hr
perazine Curve, ¿tg/hr
After Buta¬ perazine, hr
Plasma
RBC
Plasma
RBC
Plasma
RBC
23 25 26 27 27 27 28 56 29.9 ±3.8
70 320 345 260 690 310 120 119 279 ± 70
18 520 144 71 42 90 215 50 144 ±58
8.4 6.3 9.2 26.6 16.0 9.0 11.5 12.1 12.4 ±2.3
...t
0.69 3.39 4.60 4.28 15.67 2.46 4.15 1.29 4.57 ±1.7
0.07 4.20 1.90 2.10 1.15 3.60 1.26 1.16 1.93 ±.50
103 130 90 600 420 269 ±103
42 40 10 127 30 50 ±20
NS
NS
9.8 8.3 5.7 8.5 5.6 7.6 ±0.8
