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Pharmacokinetics of chlorpromazine after single and

chronic dosage

Plasma concentrations of chlorpromazine and its sulfoxide were measured aßer single
intramuscular, single oral, and multiple oral doses of chlorpromazine. In four out of nine
patients, intramuscular doses gave stable chlorpromazine plasma levels which were
maintained for 12 hr or longer. Chlorpromazine sulfoxide was found in plasma from all
patients aßer oral doses but not after intramuscular doses, whieh indicates that
suljäxidation took place presystemically. The biologie availability of single oral doses
relative to single intramuscular doses rangedfrom 10 to 69%, and was on average 32%.
After 33 days of oral dosing, the plasma levels of chlorpromazine were on average 37%
lower than might have been predietedfrom the single oral dose eurves. This was not due
to decreased biologie t! of ehlorpromazine, but apparently to a decrease in the biologie
availabi/ity by oral administration, possibly by increased presystemic metabolism.

Svein G. Dahl, Ph.D., and Roald E. Strandjord, M.D. Oslo, Nonvay
Institute of Pharmacology and Gaustad Hospital, University of Oslo

Techniques for assay of plasma levels have may contribute to the effects of the drug in pa-
now been developed for several neuroleptic tients.
drugs. Monitoring of neuroleptic drug concen- Although more than 30 metabolit es of chlor-
trations in plasma will, however, be of limited promazine have been identified,27 the plasma
clinical usefulness until more knowledge is levels of unchanged chlorpromazine correlate to
available on the relationship between plasma peripheral physiologic effects like pupil width,
levels and effects, and on the pharmacokinetics salivary secretion, and sweat gland activity in
of these drugs and their metabolites. The patients. 2t The antipsychotic effect of the
phenothiazines are converted to several differ- neuroleptic drugs seems to be related to their
ent metabolites, some of which are phar- ability to block dopamine receptors in the cen-
macologically active, but it is still not clear tral nervous system,26 wh ich is followed by in-
which metabolites have both pharmacodynamic creased dopamine turnover in the brain. lt has
and pharmacokinetic properties such that they been demonstrated that the striatallevels of the
dopamine metabolite homovanillic acid in
chlorpromazine-treated rats correlate to the
Supported by Grant B 0106.4033 from the Royal Norwegian chlorpromazine concentration in the brain. 30
Council for Scientific and Industrial Research, and by grants from
the Norwegian Drug Monopoly, the Jacob Aall Foundation, and Some clinical studies have indicated that there
Anders Jahre's Foundation for the Promotion of Science. is a relations hip between the plasma levels of
Received for publication April 12, 1976.
chlorpromazine and the outcome of the treat-
Accepted for publication Nov. 20, 1976.
Reprint requests to: Dr. S. G. Dahl, Institute of Medical Biology.
ment of psychosis, 2, 18, 19 but others have found
University of Trams\'!, N-9001 Trams\'!, Norway. no such relationship.14

437

487 333 351 0. for the chlorpromazine curves after single doses.502(29) 1. the 7-hydroxy such a process. 14 It was therefore con- CPZSO chlorpromazine sulfoxide o c1uded that chlorpromazine accelerates its own administered dose F biologie availability metabolism by inducing liver microsomal ox- fraction of intramuscular dose that idizing enzymes. however. Ao-~. A~.055(25) 814 157 222 0. is considered c1inically doses of chlorpromazine. T area under the plasma concentration curve from zero to time T after a A decrease in the plasma levels of unchanged single dose chlorpromazine has been observed after about 2 ASS 0-12 area under the plasma concentration wk of oral dosing. 24 and induction of drug curve in one dosage interval. 22 A O.11 0.39 3 29 55 I . metabolizing enzymes in the liver or in the gut which was 12 hr.11 0. body weight. 7 The plasma levels of the sulfoxide pointed out that this could be explained by a and the ratio of sulfoxide to chlorpromazine first-pass effect in the liver by oral dosing. Age.959(46) 993(33) 417 109 90 0. 21 It was later dosing plasma concentration measured at demonstrated that the fall of chlorpromazine time T after a single dose plasma levels during the first weeks of treat- Cl total clearance ment was accompanied by a shortening of the CPZ chlorpromazine half-life of antipyrine.18 0.11 0.15 0.44 8 43 82 1.49 0.l1 and it was later inactive. has been observed after intramuscular and oral promazine sulfoxide.oo . after repeated was suggested as an explanation.915(41) 1.22 6 18 83 I .27 2 47 74 836(30) 811(40) 331 131 129 0. and chlorpromazine sulf- Some studies have suggested that in addition oxide was suggested as a possible product of to unchanged chlorpromazine. the "responders" to chlorpromazine treat- tration curve after a single dose me nt.666(64) 835(38) 348 91 154 0. 20. A~~12' A 0-36.288( 19) 265(14) 186 130 76 0. and area under plasma concentration curves* Area under CPZSO Area under CPZ curve Area under CPZSO curve curve/area (ng hr/ml) (ng hr/ml) under CPZ curve Body A o. 10 . 11 Where the metabolism takes place has tt biologie half-life not.577( 18) 556(16) 478 40 90 0. 11 A different ratio of the conju- metabolite also contributes to the clinical effect gated to unconjugated metabolites in the urine of the drug.22 0.41 7 58 58 1.31 *The area extrapolated from 48 hr to infinity is given in parentheses as pereent of the tOlal area.460 838 551 133 153 0.438 Dahl and Strandjord Clinical Pharmacology and Therapeutics Table I. reaches systemic circulation as Chlorpromazine is almost completely me- unmetabolized drug tabolized in the body. chlor. It has Vß apparent volume of distribution been suggested that chlorpromazine is partially Q hepatic blood flow rate metabolized during absorption from the gas- trointestinal tract. plasma levels seem to be generally higher in Special abbreviations used patients c1assified as "nonresponders" than in total area under the plasma concen. 15.19 4 50 79 1.676(48) 688(63) 344 75 111 0. and less than 1% of fraction of oral dose that reaches the dose is excreted as unchanged drug in the systemic circulation as un- metabolized drug urine. 20 Another metabolite.12' Single Multiple Age wt single single multiple single multiple oral oral Subject (yr) (kg) im dose oral dose oral dosing oral dose oral dosing dose dosing I 59 92 764(33) 1.16 0.24 5 51 74 1. been definitely located.21. 15 ..07 0.32 Mean 44 75 1.

m • • CPZ CPZ :: WO L 100 mg ora lly • -<0 CPZ CPZSO E : 0-<> CPZSO 0\ 50 '- C • c . Plasma concentrations of chlorpromazine (CPZ) and chlorpromazine sulfoxide (CPZSO) after single and multiple doses (Patient I). After having been in· coffee. treatment. 6 mg daily. elimination of chlorpromazine and its active and Patient 7. 50 mg intramuscularly in the blood. haloperidol . a hot meal was served. The elimination rate of drugs which are neuroleptics.. l. 6. flu· clear which factors are rate·limiting in the pentixol in daily doses ranging from 3 to 6 mg.ng . . Patients 4. o ä:'" Oay Oay Oay 33 2- 151' '" I I I 8 -L -L l' t. and hepatic blood ftow. . The head psychiatrist of the hos· as the equivalent amount or concentration of pital departments in which this study was free base. The of the eight subjects are given in Table I. however . bilirubin. The first blood sampie of each series was taken patients had all been in the hospital for 1 yr or shortly before the drug was administered (0 hr) . nine patients agreed to take part. serum proteins . t o ~ 5. I •• " 6 12 24 36 12 12 o 6 12 24 36 48 Time aller dose (hr) Fig. and 8. but one and the morning doses given during the period was later withdrawn. A single 50 mg . I ! I o ! . AU medication was on which parameters are the most important in withdrawn 4 wk prior to the single intramuscu- determining the pharmacokinetics of chlor· lar dose of chlorpromazine. This study was carried out 10 gel information Experimental design. 5. Electrocardio- inftuenced by diseases causing changes in the gram. and no other drugs promazine in man. The dos es and Methods plasma concentrations are. CircIes and triangles represent the mean of two determi· nations.Vo/ume 2/ Chlorpromazine kinetics ajier single and chronic dosage 439 Number 4 PATIENT 1 200 r S. serum creatinine. and how the elimination is jects were somatically healthy. 3 1 It is not every third week. milk. Patient 3. metabolizing activity of the liver.ngle doses MulI'ple oral dos. drug binding ftufenazine enantate. after the study. and binding of chlorpromazine and its metabolites serum cholesterol were controlled before and in blood and tissues. and had been treated with various Single intramuscular dose. given here Subjects. All sub· metabolites. The tablets were taken during or conducted selected 15 female ps ychiatric in· shortly after a me al of sandwiches. according to the hospital routine . About formed about the aim of the study and the pro· 3 1h hr after administration of the single dose tocol. . alkaline liver enzyme activity. and how these parameters were given during the study. hemoglobin. I I! . 200 mg once daily.. more.'0 b '. Patient 3 received vary between individuals and during their the last ftufenazine dose 7 wk before the study. or the phosphatases . The tablets and the solution for injection con· tained chlorpromazine Hel. 2 50"'g . the cardiac output. 100 mg . o • ~ 20r ~ ~} ~ • c 10 P \ e f" . and patients for the study. The age and body weight of repeated dosing. Patients 1 and 2 received metho· metabolized in the liver may depend on the trimeprazine.

CPZ Cl--<) CPZSO E i~~ 0 . PATIENT 3 200 Single doses Multiple oral dosing. . Blood sampling and assay procedure. 3. Results in Patient 2 (see legend.5. 12. Day Day Day 33 2 8 14 15 ! 1 I I I I I I 1 !!! I I I ~ ~ I1IIIII111111 I I I 0 6 12 24 36 12 12 0 6 12 24 36 4B Time after dose (hr) Fig.5. and 36 The maintenance dosing was stopped on day hr after the injection. The patients days after the single oral dose_ A blood sampie were allowed to sit or walk as usual after the was collected shortly before the morning dose injection..3. 3. 12.-L.3. Blood sampies were collected after 0. Results in Patient 3 (see legend.8... dose. A single 100 mg oral dose Blood sampies were collected at 0. 33. . Fig.5.2. • c CII u c: .24.0 CPZSO cn c: 50 c: 0 • • "@ cCII o o u c: 0 u <lJ E 5 111 !!l Il. CPZ :::. Oral maintenance cubital vein into heparinized polyethylene dosing with 100 mg twice daily was started 2 tubes..8.24. 2. dose was injected intragluteally.. Blood sampies were collected 0.0 CPZSO cn c: c: 0 '@ . 1. Fig. A 5 2. and 36 hr..8. to 10 ml sampie of blood was collected from a Repeated oral dosing. when only the morning dose was given.. and 48 hr after the last dose.100 1. . Day Day Day 33 2 8 14 15 I ••••• I ••••• I I -1. CPZ .24.. (12 hr after the evening dose) on days 8 and 14_ 0.4.4. 1.6.100 100 mg orally _ CPZ 0-0 CPZSO E 0 .~ u <lJ E 5 111 0 !!l Il.---. 100mg x 2 50 mg i.0. 1.4.---..5. and the plasma . CPZ _CPZ :::.6. was given 1 wk after the single intramuscular 6.. • 0 10 .25.m.m. I). 100 mg orally . 12. 1. immediately centrifuged.36. I ••• !! I!!!!! I o 6 12 24 12 12 0 6 12 24 36 48 Time after dose (hr) Fig.. 100mg x 2 50 mg i. Single oral dose.2. 1).440 Dahl and Strandjord Clinical Pharmacology and Therapeutics PATIENT 2 200 Single dos es Multiple oral dosing.

. "---A CPZ .1". PATIENT 5 200 Single doses Multiple oral dosing..~I~"u'~'L. CPZ cpzsa cpzsa • 0-0 0-0 • o c o CIJ u C o u <ll E 11\ <ll !L Day Day Day 33 2 8 14 15 [ " ... Pharmaeo. I). Fig.. IDDmg x 2 50 mg Im A---A CPZ _CpZ 100 mg orally ..5 assuming one day. CPZ <>-<> cpzsa E <>-<> cpzsa Ol c 0 c • o ~ ----4- c C1J ---& • u c 10 0 o u <ll E 5 11\ <ll CL Day Day 2 8 14 15 1"".. An indwelling cannula kinetie eonstants were ealculated for eaeh sub- was used for the 9 or 11 sampIes taken during jeet by previously derived equations. CPZ ::. Two aliquots from the same plasma sampie were analyzed on different days..J~______~1______~LI______~I o 6 12 24 36 12 12 0 6 12 24 36 48 Time after dose (hr) Fig. frozen in two aliquots.m. Fig.. 5. eurve (A O. 1). Plasma sampies were promazine.1 I 1 -L-L- o 6 12 24 36 12 12 12 24 36 48 Time after dose (hr) Fig..Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 441 Number 4 PATIENT 4 Single doses Multiple oral dosing. .100 IOD mg orally .. IU'~'L"U.. 1 1 1 -L -L.24 0 C until analyzed by a gas. IOD mg x 2 50 mg i..T ) was ealculated by the trapezoidal Pharmacokinetic calculations. rule. .. stored at .. and a Wassermann ne edle was used first-order kinetics for the elimination of ehlor- for the other sampIes . " [ " . Results in Patient 5 (see legend. 4. . Total area under the single dose eurves: chromatographie method 6 based on flame ioni- sation deteetion. Results in Patient 4 (see legend. with two injeetions into the gas ehromatograph The area under the experimental part of the for each plasma aliquot..

Total clearanee.!'-'--'-!6~.. after the injeetion. and Estimates for the biologie t! for chlor. The mean t! followed by a relatively rapid fall-off in the after the single oral dose and the single in.!E o o Cl.J.442 Dahl and Strandjord Clinical Pharmacology and Therapeutics PATIENT 6 200 Single doses Multiple oral dosing. CPZ ::. 15 or 30 min after the intramuseular injeetion in relative to single intramuseular doses: all but Patients 2 and 7. 2.. "---6 CPZ .1 12 12 0 6 12 24 36 48 Time after dose (hr) Fig.100 100 mg orally . .-. c o "§ 20 C 41 u C ---A • o u • ro E 5 111 . the intramuseular dose. The t! was detennined intramuseular dose. and were hr after the last maintenanee dose. respeetively. 6. for single and Results multiple doses: As already noted. Highest plasma A~"12 . the ehlorpromazine plasma Firn (Ao-oo/D)im level was relatively stable for 24. In 2 eoneentrations of ehlorpromazine was observed Biologie availability of single oral doses... from the logarithms of the three eoneentrations Single oral dose.. to 8. V ß/F = • (5) Single intramuscular dose..-.. 100 mg x 2 50 mg i.. Day Day 2 8 14 1. relative to promazine and ehlorpromazine sulfoxide after F.m. and ehlorpromazine were usually seen 2 or 3 hr after from the four eoneentrations measured 12 to 48 administration of single oral doses. 7. and 8. who did not reaeh the maximum until 4 hr after the injeetion. promazine sulfoxide was not traeed in any timate were ealculated for eaeh subjeet by linear plasma sampies from the nine subjeets after the regression analysis.oo • In 2 Table I.~ \ <>---<> C pzsa c 50 "&. CPZ C>--O cpzsa E Ol ~ .. 12. 1) for eaeh subjeet. 12 hr. 36.J.1"". Results in Patient 6 (see legend. I). one of the nine patients D relapsed and had to be withdrawn after the first CI/F = (2) A o. together with the age and body weight o . Peak eoneentrations of measured 12 to 36 hr after the single doses. I D· t. The areas under the eurves are presented in Vß/F = ' (4) A o.5 OLw. Chlor- promazine and the standard deviation of the es. but (Eq.. t.. In Pa- F po (Ao-oo/D)po (6) tients 1. for single and multiple doses: single and multiple doses are shown in Figs. tramuseular dose was used in estimating the Chlorpromazine sulfoxide was found in plasma area under the extrapolated part of the eurves from all patients after the single oral dose. always in lower eoneentrations than the parent . relative to F. of the patients. . The D others were in a stable mental eondition C!/F = (3) throughout the drug-free period and the rest of A~"-:2 the study. Fig. Plasma eoneentrations of ehlor- Apparent volume of distribution.."..J':----::-'-------=. -L---L 1..oo part of the study. plasma eoneentration during the next 3 to 6 hr.

-A.'U'-'-'_L.-.I-'-'-'-"-'--'-'-'--'-LL-_ _ _-::-IL-_ _ _-II -L ----L lu'-.5 .''u'~I-. The areas under the sulfoxide curves dosing. •~ -.--. areas under single and multiple oral dose Repeated oral dosing.. I). PATIENT 8 200 Single doses Multiple oral dosing. 100mg x 2 50 mg I. Fig. and was on average 37% in all eight pa- 4.----. GI u ~ 10 -..--6 • • C o u <0 o o ~ 5 <0 CL Day Day Day 33 2 8 14 1.-.. CPZ .m . curves in all subjects. 3. Fig. epz =100 100 mg orally _ epz <>-<> CPZSO E <>-<> epzso C1l C c o iii '- C GI u ~ . Results in Patient 8 (see legend.-.. smaller curve to the area under the chlorpromazine . 100 mg x 2 50 mg i.Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 443 Number 4 PATIENT 7 200 Single doses Multiple oral dosing. however.._--- ~ c 20 -.. Results in Patient 7 (see legend.'I':--_ _ _~I_ _ _---=-'-::'_ _ _-----. morning dose were either higher (Patients I. and 8) on day 33 than on day 8 of repeated tients. 5. • • u o Day Day Day 33 2 8 14 -uu~~~~---~2-L. plasma concentrations measured before the ranged from 14% to 59% in the others. Iower (Patients 2. The ratio of the area under the sulfoxide of maintenance dosing were. I). .---.---. or virtually within one dosage interval were on average unchanged (Patient 7). drug... 7.m. The difference in ing chlorpromazine curve (Table I).. epz -CPZ = 100 100 mg or ally e---e ePZ 0----<> CPZSO E 0-0 cpzsa C1l c 50 c o . and 6).'1 o 6 24 36 12 12 0 6 12 24 36 48 Time after dose (hr) Fig.. 8... Chlorpromazine curves was only negligible in Patient 4..-'_L.4-----'36 ~ 1T Owl'~'~'w"~~~'u"~'-'-'1~2-----=-2~~---~3~16~-----t8 Time after dose (hr) Fig. The area under sulfoxide curves were on than the total areas under the single oral dose average 18% of the area under the correspond. The areas under the 3 I % of the areas under the chlorpromazine curves within one dosage interval after 33 days curves.

In only one eoneentrations after intravenous injeetion of 25 ease (Patient 5. 7.6 3 18 17. whieh may explain why the esti- were five eases of fainting.444 Dahl and Strandjord Clinical Pharmacology and Therapeutics Table 11. The estimates The shape of the plasma level eurves ob- of biologie availability of ehlorpromazine after served after intramuseular injeetion in Patients single oral doses.2) 0.3 5 25 43.8) 14.2( 2.5(12.3) 30. 12 hr after the were therefore only approximately estimated (in intramuseular dose. As may be seen from Figs.9( 1. are refleeted in an inerease in Beeause of the apparently slow absorption of Cl/Fpo and Vß/Fpo from single to multiple oral the drug after intramuseular injeetion.9 7 25 78.0(32. The differenee in this ratio were seen du ring the period of repeated dosing.9(21. and 8 indieate that the drug was slowly lar doses.2( 5.3) 20. estimated from average plasma eentrations were above 100 ng/ml. No other adverse reaetions were noted after the single oral dose in all subjeets exeept after the single doses.2( 1.2) 0. relative to single intramuseu. 2.2) 27.6 27. Biologie half-life (with standard deviation in parentheses). was mg in 13 subjeets. apparent volume of distribution.4) 24.8 35.7( 7.9( 3.44 14. between single and multiple oral doses was signifieant (p < 0. absorbed from the site of injeetion.4 22.4) 34. dose eurves.3 8 21 14. The smaller areas under the eurves within ng/ml for 24 hr in one patient. Pharmaeokinetie parameters for ehlor- eurred when the ehlorpromazine plasma eon. and no adverse reaetions Patient 6 (Table I).6) 0.1 28. the extrapolated part eomprised 64% the single oral dose.8) 0.0( 9. The total area 0.3 hr after Patient 7. in another patient one dosage interval after repeated dosing.53 13. there a plasma eoneentration above lOO ng/ml whieh is eonsiderably smaller than most of the without eoneomitant fainting after a single values for Vß/Fim given in Table H.8 Mean 32 31.8) 103. Patient 4.1( 4.3( 2.50 30. Discussion Pharmaeokinetie eonstants. I hr after the oral dose).2( 4. I to 8. Patient 6.2 41. There after 12 hr.0 26. 1.09 22. distribu- dosing. always after single mates of biologie t! were longer after single oral or intramuseular doses: Patient 3 fainted intramuseular than after single oral doses in all 0.7) 15. of the area). tion equilibrium may not have been attained Plasma levels and adverse reactions.0 6 10 18.5 hr after the .3 26.8) 17. whieh has The apparent volume of distribution and the already been reported 3 : After intramuseular in- total clearanee for ehlorpromazine.43 17.65 9.5 hr after the intramuseular dose.6( 6.6 35. ranged from 10% to 69% (Table II).3 30.0 2 49 20.2( 1.1) 15.1 4 39 32.3) 1.3) 21.3) 1.5 30.8 eurve was higher after repeated dosing than dose.16 show a Vß of 8.01) by the sign test.9( 2.0) 14.1) 58.3(29.50 35.3 30. 3. relative to jeetion of 100 mg of ehlorpromazine the plasma its biologie availability.64 20.8) 1O. but Patients 2 and 8 (Table 11).8( 7.00 23. is also given in Table eoneentrations fluetuated between 55 and 78 H.2) 0.9) 47.1( 1.5) 0. eom.2( 1.1 L/kg. and Patient 7. prornazine.6(43. This might . the highest plasma eoneentration was measured pared to the total areas under the single oral 6 hr after the injeetion.4 0. all these eases but one (Patient 6) oe.intramuseular dose and I hr after under the eurves after intramuseular injeetion the single oral dose. and total clearanee for ehlorpromazine t! (hr) Single doses F po Firn Mean Multiple Cl/Fim VßIF im Subject (0/0) lntramuscularly Oral value dosing (L/min) (L/kg) 1 69 25.2( 1.2( 1.

If the reduetion in dose. the sulfoxide eould nevertheless in agreement with previously pub.5 32.6 196. Although the estimates of .8. tion eurve within one dosage interval at steady promazine by oral administration eould be due state will be equal to the total area under the to ineomplete absorption. Substitution of Q = 1.9 absorption or by metabolism prior to or during 6.05 31.06 5. 67%.0 186. Our results are took plaee only in the gut. during enterohepatie reeireulation of the sorption of ehlorpromazine from tablets was on drug. and it did Llmin and the values given in Table I for Ao. tion (F po ) therefore was lower than the values However. still be formed after parenteral administra- lished data.8 42. signifieantly smaller. 67%. eompared to the areas under the single oral dose eurves (Ta- F = I _ 0 (7) ble I).49 74. sinee the estimates of (Ao-oo)im may have been smaller than the areas under the eurves after Single Single oral Multiple oral Multiple an intravenous injeetion of the same dose.6 158.4 The faet that no sulfoxide appeared in plasma 2. The reduetion in the total areas under an intravenous injeetion of the same dose and the single oral dose eurves was not very great (2) transfer of the drug to the liver was blood when the half-life values from these eurves flow rate-limited. whieh indieates that a signifieant part I. eould be due either to a deerease in ti' a (AO-oo)im .97 95. and the available dose by oral administration were the biologie t! of the drug are unehanged. metabolism in the eurve after a single dose. 7 yield the under the eurves after repeated dosing were following values of F for Patients 1 to 8: 1. Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 445 Number 4 27%.29 8. and to of drug reaehing systemie eireulation from eaeh a first-pass effeet in the liver.12 36.79 141. 57%. the The smaller areas under the plasma eoneen- biologie availability might be estimated by the tration eurves within one dosage interval after equation: 9 33 days of maintenanee dosing.5 were used instead of the mean values. 6.5 whieh gave even intramuseular doses was underestimated.oo not invalidate the eonclusion that the areas after the intramuseular dose into Eq.0 131.6 stantially higher than the values obtained for 2. the apparent volume of distribution. 7. These figures may be overestimating the influenee of a eontingent Cl/Fpo V ßIFpo (L1min) (L1kg) first-pass effeet on the biologie availability.03 48. 7 were sub- 1. 4. 72%. II 1.52 4.29 80.68 4. provided the amount gastrointestinallumen or in the gut wall. 25. in Patients 3 to 8 the bio- availabilities ealculated by Eq.58 2.7 gests that the sulfoxide was formed in the gas- trointestinal lumen or in the intestinal wall.3 the proeess of absorption.00 67. 2. if sulfoxidation of ehlorpromazine obtained for Fpo/Fim (Table II). Similar observations have been reported for the indieate that the total area under the eurves after eongener methotrimeprazine.12 whieh show that the extent of ab. 34%. 71%. neties that the area under the plasma eoneentra- The relatively low bioavailability of ehlor. dose dosing dose dosing Nevertheless. than of the parent drug after single oral doses.00 3.42 4.8 254.84 149. 3. Q deerease in Fpo ' or an inerease in Vß. 5.00 4.0 after single intramuseular doses strongly sug- 2.8 179.6 3.6 246. 28 average about 25% of that from doses given It is a general prineiple in linear pharmaeoki- intramuseularly. and higher plasma eoneentrations of the sulfoxide that the biologie availability by oral administra.7 of the oral doses was lost either by ineomplete 1. 65%. tion. 2. It may be This equation is based on the assumptions that noted that the mean t! values from single in- (1) in eaeh individual the area under the plasma tramuseular and oral doses were used to ealeu- eoneentration eurve after an intramuseular dose late the area under the extrapolated part of the would be equal to the area under the eurve after eurves.4 Fpo/Fim . and 8. 29 entirely due to a first-pass effeet in the liver.

at least Chlorpromazine-treated rats had chlor- in part. 20 tend to be associated limiting process in the hepatic elimination of with a poor response. Some the gut could be due to induction of drug have found no correlation between chlor- metabolizing enzymes in the gut wall or to promazine plasma levels and clinical effects. 23 plasma levels of chlorpromazine 2 • 19. dence offainting after single oral or intramuscu. Thus. It has The most plausible explanation for the rela. substan. a well-known clinical trations of chlorpromazine and its sulfoxide experience that tolerance to acute side-effects have been measured in two psychiatric patients. as promazine in plasma on day 33 of repeated dos- shown in Table H. promazine between plasma and the brain. If the been found. 30 The striatal ible. 30 This reflects the changes in the binding of the drug to plasma or individual variation in the distribution of chlor- tissue proteins . although the latter dosage scheme would the observation that the ratio of area under sulf. as high as in the plasma. sponse and drug concentration at the site of ac- crease in the plasma levels of chlorpromazine tion. however. ing (Fig. This may be due to individual dif- drug is subject to first-pass metabolism. explanation for the increase in Cl/Fpo from homovanillic acid levels correlated to the brain single to multiple oral doses is that the apparent levels of the drug. who after the single oral dose and that the observed fainted after single oral doses although both had increase in Cl/Fpo from single to multiple doses about the same peak concentrations of chlor- was due to an increase in the ratio Vß/Fpo . This was cor- was not shorter after 33 days of oral dosing than roborated in this study by Patients 4 and 7. It is. without reducing markedly the and in the relationship between therapeutic re- biologic t! of the drug. but not to the plasma drug volume of distribution was increased due to levels after repeated dosing. have been due to enzyme induction in promazine concentrations in the brain 10 times the liver. be expected to give significantly high er peak oxide curves to area under chlorpromazine concentrations in plasma after each dose. Cerebrospinal fluid and plasma concen- lar doses. 22 and the lt has been demonstrated 17 that the rate. duced by neuroleptic drugs may develop within precise. like drowsiness and fall in blood pressure in. vidual differences in the binding of the drug to tion of unchanged chlorpromazine and the inci. from single to multiple oral doses may.446 Dahl and Strandjord Clinical Pharmacalagy and Therapeutics t! (Table H) must be considered relatively im. and the liver. and vice versa. Another possible. the relative de. previously been reported 13 that no differences in tive decrease in the plasma levels after multiple the benefit of the treatment or in the occurrence dosing seems to be that the biologic availability of side-effects were seen whether daily chlor- of the drug was decreased due to increased me. one who responded weil to chlorpromazine . it may be concluded that the biologic t! a few days of repeated dosing. however. although less plaus. 7-hydroxy metabolite l5 . 1) without adverse reactions. curves increased from single to multiple doses Several studies of the relationship between for aB subjects except Patient 6 (Table I). the dis- induction in the liver may. plasma proteins and tissue constituents. 4 . This The results from our study indicate that there variation is probably in the main due to indi- is a correlation between the plasma concentra. oral dosing. This explanation is supported by dose. promazine doses of 150 mg or 300 mg were tabolism in the gastrointestinal lumen or in the given as three doses a day or as one evening intestinal wall. The plasma levels and therapeutic response to apparent increase in the extent of metabolism in chlorpromazine have been performed. Almost all highly distributed drugs may be the transfer of report large individual variations in chlor- the drug from peripheral body compartments to promazine plasma levels relative to dose. tribution of the drug and its metabolites be- tiaBy decrease the plasma levels obtained by tween plasma and the central nervous system. changes in intrinsic hepatic no clear-cut correlation between plasma levels clearance by enzyme induction will have little and response to chlorpromazine treatment has effect on the biologic ~ of such a drug. enzyme ferences in the pattern of metabolism. 14 adaption of gastrointestinal microorganisms to whereas other studies have indicated that low the drug. Thus.

. J. Commun. L. S. 15. Sei. Jacobsen at the Institute of Phar.. References 14. 191: 17- cerpta Mediea ICS 180. J.: The possible role of metabolites in plasma. centrations were. Areh. F. W. about the same CSF/plasma concentration ratio 121:8-12. H . 16. and Kanter. M. 3.... S. Plasma levels and urinary excre- study and Or. and Curry. Syst.: Influenee of first-pass effeet on avai1ability of Such observations suggest that the lack of corre- drugs on oral administration. 1975. and Ma1ing. L. Castaiieda.Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 447 Number 4 treatment and one "poor" responder. Sci.. Davis. J.: and MarshalI. and Lader.. I. M.: Clearance and and Bove. D. J. R. and Baker. Ther. P. therapeutic response to ehlorpromazine treat- 7.: Interpatient variation in Plasma disappearanee and cerebral effeets of physiologieal availability of ehlorpromazine as a chlorpromazine in cirrhosis. Dis. THER. Pharmacol. Janowsky. 8.. G. Pharm. H.. H. Amsterdam. 1974. and Mrs. Psyehiatr. Dahl. considerably lower E. H. 1973. J. P. 13. S... Gershon. S. D.. Nervenkr. 1970. G... Pharmacol. ute to the effects of the drug. Derr. CUN.. Rivera-Calimlim. L. 19:323-329. 20. 4.. G. tients. and Feldman. 0. Pharm.. S. 1975.. Sakalis. S.: The relationship of plasma chlorpromazine to report on elinical response and blood levels of its 7-hydroxy and sulphoxide metabolites in a chlorpromazine and its sulfoxide during ehlor. A. The authors wish to thank Or. 17. S. M. 24. Clin. J.. Williams. Ellefsen. S. S.. J. Exp. P. L. 65:1329-1333. J. Ex. E. 19:435-442. and Kaul. ment. 1966. in the rat and dog. E. and c1inical effects may not be explained solely 10.: Pharmacokinetics of methotrimep. Eur.: 18. R. Clin. Novick. Pathol. J. 2:197-208. J. the patients who volunteered. Hollister.. Curry. promazine administration.24 and it is not yet ing single doses and in steady-state conditions. PHARMACOL. 1976. M. M. T. N. T. H. V. M.. and Feldman. A. M. concentration of chlorpromazine sulfoxide. N.. Phar- to the central nervous system. S. however.. metabolism and clinical effeet. 43: 143- complicating factor in eorrelation studies of drug 151. 1969. Davidson. P. J. 12. D. Dahl. Pharmaeol.: Action and metabolism of chlorpromazine 21..1975. PHARMACOL. Derr. 11. lation between chlorpromazine plasma levels 60:1338-1340. pp. Curry. responder. W. J.. 1962. Bruek. 2. and Gibaldi. Exp.: Route of admin- by differences in the distribution of the drug istration and drug metabolism. Parkes. Med. S.. Pharmacol. Sakalis. Clin. 1957. S. man. S. editors: The present status of biologic half-life as indices of intrinsie hepatic psychotropie drugs. Psyehopharmaeol. Sei. Boyes. and 5. S. Psyehopharmacologia 32:279-284. and . 14:978-986. L. J. M. tion of four different dosage forms of chlor- macology for valuable discussions on the results and promazine.: Effects of mode of management on razine after single and multiple doses.. and Nordgren. and Van Loon. A. L.. Exp. J. L.. 11:28-30. J. JÖnsson. Br. J.. H. Soe. V. and tion of methotrimeprazine and its sulfoxide in Park. H. G. M. S.. S. Bull. CUN. 1:425-530. 9. Rondish. Mackay. Res. 1971. Flanagan. promazine therapy in ehronie schizophrenie pa.: Bilary and urinary exeretion patterns of in the "good" responder than in the "poor" ehlorpromazine in the dog. Julia E.. 134:314-318. M. L. Rystad for Therapeutie effects of different modes of chlor- skillful technical assistance.. Br. Clark. S. Psychopharmacol. L. 1976. Loga. 1 Both had sulfoxide in man. Carrella.. plasma chlorpromazine in psychiatric patients. Several differ. Mould. Lin. S. 1973. J. large population of ehronie sehizophrenics.: GLC determina.. Mould. Bremer at Gaus. L.. F. in Cerletti. Ther..: Urinary ent chlorpromazine metabolites accumulate in exeretion of ehlorpromazine metabolites follow- plasma by chronic treatment.: Morsund. The chlorpromazine con- J. Biol. Nerv. and Sjoerdsma. Gibaldi.: Interactions I. 2:330-338. and Hsu. Healey. Gibaldi. 11:49- in the planning of the study. CUN. Lasagna. metabolism.. who showed remarkably high CSF 51:833-836. 72-76. Hrushka. A.. Pharmaeol. 27:522-527. E . H. 19.: Studies of delayed-action tad Hospital for his helpfulness and interest in the medieation. L. Proc. 1. macol. L.: Plasma chlorpromazine in The physiologieal disposition of chlorpromazine psychiatrie management. L. L. J. 221:167-170. S.. Maxwell. G. 1972. THER.. T. G. and Curry. We are also indepted to 59.: of orphenadine and phenobarbitone with chlor- Cerebrospinal fluid levels of chlorpromazine promazine: Plasma eoncentrations and effeets in and its metabolites in sehizophrenia. Chan. Bull. Chem. Sci. Curry.. Terry. S. 1971. THER. Curry. 6. 1972. c1ear to what degree and how each may contrib. H.. and Jaeobsen. Axelsson. Curry. Perrier. Rivera-Calimlim. of chlorpromazine. 11:76-77. Mrs. L. PHARMACOL. 1974.: A preliminary J. Pharm. 1975. Hollister.. Reyno1ds. S. D. 1970. and to Miss T. E. M.

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