European Journal of Clinical Pharmacology

Europ. J. clin. Pharmacot. 11,305-310 (1977)

© by Springer-Vcrlag 1977

Pharmacokinetics and Relative Bioavailability of Levomepromazine after Repeated Administration of Tablets and Syrup S. G. DahP, R. E. Strandjord 2 and S. Sigfusson2 ~Institute of Pharmacology, and 2Gaustad Hospital, University of Oslo, Oslo, Norway

Summary. Plasma levels of levomepromazine and its sulphoxide were measured in 8 psychiatric patients after repeated doses of levomepromazine tablets or syrup. The rate and extent of absorption of the drug were similar for the two dosage forms, although the extent of presystemic metabolism appeared to be slightly greater after administration of syrup than of tablets. The biological half-life of levomepromazine ranged from 16.5h to 77.8h, and a 13-fold variation was seen in the ratio of the total clearance to the absorbed fraction of the dose (Cl/Fpo). It is postulated that individual variation in the dose required for therapy was due in part to individual variation in the pharmacokinetics of the drug. Key words: Levomepromazine, levomepromazine sulphoxide, plasma levels, biological half-life, total clearance.

plasma levels, clearance and biological half-life of levomepromazine in a larger number of patients than the 5 of the first study [1].

Material and Methods

Subjects Eight psychiatric patients volunteered to take part in the study after having been informed of its aims and protocol. All had taken levomepromazine tablets for at least 4 weeks, and none were receiving any other drugs. The patients were clinically well and had normal ECG, haemoglobin, serum creatinine, alkaline phosphatases, bilirubin, serum proteins and serum cholesterol.

Experimental Design General information about the pharmacokinetics of levomepromazine in man has recently been published [1]; levomepromazine sulphoxide appeared to be formed presystemically, and plasma levels of sulphoxide were higher than the level of the parent drug after oral administration. Subsequent in vitro studies [3] showed that levomepromazine sulphoxide was pharmacologically active in producing cardiac effects. The relatively large extent of sulphoxidation after oral administration may be clinically relevant, therefore, beyond its influence on biological availability of the parent drug. The aims of the present study were 1. to compare the rate and extent of absorption and the extent of sulphoxidation of levomepromazine administered as tablets or syrup; and 2. to gain information about

Levomepromazine tablets and syrup were taken during or shortly after a meal of sandwiches, milk, and coffee, according to the hospital routine. The syrup and tablets contained levomepromazine hydrochlofide; the doses and plasma concentrations quoted here represent the equivalent amount or concentration of free base. Before the study commenced, some of the patients had received larger doses of levomepromazine tablets in the evening than in the morning. During the study each patient received the same amount of levomepromazine daily as before, but I week prior to blood sampling, the daily dose was divided into equal morning and evening parts, which were given at a 12 h interval. After 1 week of treatment with equal morning and evening doses of levomepromazine tablets, the medi-

S. G. Dahl et al.: Pharmacokinetics of Levomepromazine

306

40OF_

400

PATIENT 1

300~Dose: SOmg x2

Syrup: Tabtets:

200~-

~ll .......... 0 6

LM LMSO H m--= o--o

I

I

I

12

24

36

PATIENT 2

300F

D.... 50mgx2

I,,,~,1

_.. l

....

6

48

,t

12

400-

PATIENT 3

300

Dose;25mg x2 200

Syrup: Tablets:

L

LMSO

I

I

24

36

_ _ l

48

Time a f t e r dose ( h r )

Time a f t e r dose ( h r )

400

Syrup:

E

PATIENT 4

300~-

LM LMSO H o--o e--m o--o

Lid LMSO

~200~-

Dose: 100rag x 2

p.-~

Syrup:

Tablets :

~..

e-e o--o a--llo--o

Am

i s07"

uo

R"

E

2U ..... 0

i ..... I 6 12

I

i

24

36

5

2 48

Time a f t e r dose ( h r )

'ill....

....

.....

t ..... ~ 6 12

1 24 Time after

I 36 dose

I

48

(hr)

Fig. 1. Plasma concentrations of levomepromazine (LM) and levomepromazine sulphoxide (LMSO) in patients 1-8 after maintenance treatment with levomepromazine syrup or tablets. Each symbol represents the mean of two determinations

cation was discontinued and blood samples collected for 48 h. Maintenance dosing with levomepromazine syrup was then begun immediately, with the same dose of levomepromazine as in the preceding week. Treatment was again discontinued and blood samples collected for 48 h after 1 week of dosing with syrup. Blood Sampling and Assay Procedures In both series a blood sample was taken shortly before the morning dose (at Oh), and 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, and 48h after dosing. No drugs were given during the sampling period. Blood, 5-10ml, was collected from a cubital vein into a heparinized polyethylene tube, immediately centrifuged, and the plasma frozen in two aliquots. An

indwelling cannula was used for the first 9 samples which were taken during one day, and a Wasserman needle for the remaining samples. The plasma samples were stored at - 2 4 ° C until analyzed by a gas chromatographic method [2]. Two aliquots from the same plasma sample were analyzed on different days, and two injections into the gas chromatograph were performed for each plasma aliquot. Pharmacokinetic Calculations The total clearance (C1) of levomepromazine, relative to the fraction of the administered dose that reached systemic circulation as unchanged drug (Fpo), was calculated from the equation [8]:

S. G. Dahl et al.: Pharmacokineticsof Levomepromazine 400~300[/ 200~'__~~

PATIENT 5 Dose: 175mg x 2

Syrup: Tablets

-

~,00~,,~ ~ c

o

307

300 Dose:

e--e O - - O

:

~

........

"'~,. ~ ' - . . ".' - - .

175mg x 2

!

LM LMSO H I - - I ~--o

Syrup: Tablets:

200

~,,oo

'm

50

PATIENT 6

400 LM LMSO H H

~'1o.

g SO "'tl ...............

oe 2 ~ o E

F ' ~ ---

"'-

"...............

10

"

-

'

°

~

O

~ 20 ~

t0

t~ 0.-

,,,~I

0

.....

I 12

6

I

I

I

24

36

48

..... 0

~. . . . . I 6 12

Time after dose ( h r )

400-300 ~i" j°'o.

PATIENT 7

LM LM,$O Dose:

_2oo~-/~%~

so~-,

Syrup : Table,s

c~ tO0 k,r : ',%

o

75rag x 2

8

O--a

.... ,

-......-~..

~

Dose= ?5rag x2

200

~.°

I

36

I

48

PATIENT 8

40030!0

.................. ~

-"-~

c E

H

I

24 Time after dose ( h r )

Syrup= Tabtets :

LM LMSO H O--O m-~ o--o

~100

.Co s0

........ o .................

i ......

:.. .........



E

20

~ E

20

o j ~

~o

~o

! .....

I .....

0

6

C1/Fpo =

t

12

, I

24 Time after dose ( h r )

t

36

.............

t

48

D As~

The area under the plasma concentration curve in one dosage interval (As~) was calculated by the trapezoidal rule. D is the administered dose. Estimates of the biological half-lives of levomepromazine and its sulphoxide were calculated for each patient by linear regression analysis of the logarithms of the plasma concentrations measured 12 to 48 h after the dose.

Results

The admininistered doses and the observed plasma concentration curves are shown in Fig. 1. The plasma

] .....

I .....

0

6

I

12

24 Time after dose ( h r )

36

48

concentration of sulphoxide was higher than that of its parent drug in all patients. In 6 patients the plasma concentration of levomepromazine varied in a similar manner between 30 and 120ng/ml during the first 12 h after the dose, even though the daily dose in these patients ranged from 50mg to 350rng. The peak concentration of levomepromazine was usually reached after 2 to 3 h and there seemed to be no significant difference between the rate of absorption after administration of syrup or tablets. The areas under the plasma concentration curves during the first 12h after the dose are presented in Table 1. The areas under the levomepromazine curves were larger after tablets than after syrup in 5 patients; the average in all patients was 2.5% larger after tablets than syrup. The areas under the sulphoxide curves

308

S.G. Dahl et al,: Pharmacokinetics of Levomepromazine

Table 1. Age, sex and body weight of subjects and area under plasma concentration curve in one dosage interval. LM: levomepromazine. LMSO: levomepromazine sulphoxide Subject

1 2 3 4 5 6 7 8 Mean value

Sex

F F F F M M M M

Age

Body weight

LM As, (ng h/ml)

Ass Tabl.

LMSO Ass (ng h/ml)

Ass TaN.

A~ (LM) A~s(LMSO)

(yr)

(kg)

Tablets

Syrup

A~ Syr.

Tablets

Syrup

A~ Syr.

Tablets

Syrup

60 48 80 57 37 46 61 49

92 74 67 62 85 81 81 96

687 325 700 349 591 760 775 855

441 254 792 253 510 846 981 831

1.56 1.28 0.88 1.38 1.16 0.90 0.79 1.03

1290 1070 1021 1634 1736 2348 1616 1126

1425 941 1171 1435 1746 2927 2202 1363

0.91 1.14 0.87 1.14 0.99 0.80 0.73 0.83

0.53 0.30 0.69 0.21 0.34 0.32 0.48 0.76

0.31 0.27 0.68 0.18 0.29 0.29 0.45 0.61

55

80

630

614

1.12

1480

1651

0.93

0.45

0.39

Table 2, Biologicalhalf-life of levomepromazine (LM) and levomepromazine sulphoxide (LMSO); (standard deviation in parentheses), and total clearance relative to biological availability of levomepromazine

Tv2 (h)

LM: Cl/Fpo (1/min)

LM

LMSO

Subject 1 2 3 4 5 6 7 8 Mean value

Tablets

Syrup

Mean value

Tablets

Syrup

Mean value

Tablets

Syrup

Mean value

17.7 (2.3) 14.3 ( 3.4 24.9 (3.5) 20.2 (0.9) 28.6 (5.8) 60.3 (23.9) 22.4 (4.6)

15.5 (1.7) 18.7 (3.5) 77.8 (5.8) 25.0 (5.3) 26.1 (4.8) 19.3 (3.8) 41.0 (13.1) 35.9 (9.1)

16.6 16.5 77.8 25.0 23.2 24.0 50.7 29.2

20.6 (2.2) 18.6 (2.6) 31.6 (5.3) 11.9 (1.5) 19.3 (3.2) 19.1 (4.5) 18.3 (5.3) 26.4 (2.3)

I9A (4.3) I7.8 (4.1) 31.2 (3.6) 14.2 (2.1) 20.3 (4.1) 17.9 (2.7) 31.3 (11.0) 31.5 (13.1)

19.9 18.2 31.4 13.1 19.8 18.5 24.8 29.0

1.21 2.56 0.60 4.78 4.94 3.84 1,61 1.46

1.89 3.28 0.53 6.59 5.72 3.45 1.27 1.50

1.55 2.92 0.56 5.68 5.33 3.64 1.44 1.48

26.9

32.4

32.9

20,7

22.9

21.8

2.63

3.03

2.83

were smaller after tablets than after syrup in 6 patients, and were on average 11.6% smaller in the whole group. These differences were not statistically significant. Nevertheless, the ratio of the area under the l e v o m e p r o m a z i n e curve to the area under the sulphoxide curve was larger for tablets than for syrup in all patients, as shown in the two last columns of Table 1. This difference between syrup and tablets was highly significant (p < 0.005) by the sign test. T h e biological half-life of l e v o m e p r o m a z i n e ranged from 16.5h to 77.8h (Table 2). The apparent biological half-life of the sulphoxide ranged from 13.1h to 31.4h, and on average its half-life was two thirds of that of the parent drug, T h e total clearance of levomepromazine, relative to its biological availability (C1/Fpo), ranged from 0.53 1/min to 6.59 l/rain (Table 2). The lowest value of

C1/Fpo was observed in Patient 3, who showed the longest biological half-life of the drug. The average value of C1/Fpo in all subjects was 13% lower after r e p e a t e d administration of tablets than of syrup; this difference was not statistically significant.

Discussion

Substantial differences in biological half-life and apparent volume of distribution after changing from tablets to syrup would not be expected, since all subjects had b e e n treated continuously with levomepromazine for at least 4 weeks before the study. The 13% lower m e a n value of C1/Fpofor tablets than for syrup m a y therefore indicate a small difference in biological availability. Still, there was no significant difference in

s. G. Dahl et al.: Pharmacokineticsof Levomepromazine the extent or in the rate of absorption of levomepromazine, as the average plasma levels, the time before the peak was reached after each dose, and the variations in plasma concentration within the dosage interval were similar for syrup and tablets. Thus, no change in the dosage scheme should be advised by changing from one of these dosage forms of levomepromazine to the other. The plasma concentration curves for Patients 3, 4, and 5 (Fig. 1) might suggest that the rate of absorption of levomepromazine was rapid during the first hour after administration of syrup, but not after administration of tablets, when given with food. In a previous report [1], however, 2 out of 10 curves indicated that the absorption of levomepromazine was negligible during the first hour after administration of syrup. A lag time of 1 to 3 h is scarcely of clinical relevance in maintenance therapy with this drug. In acute cases, intramuscular administration of levomepromazine, which provides more rapid absorption [1], may" be more suitable than tablets or syrup. It has previously been demonstrated that sulphoxidation of levomepromazine in man mainly takes place before the drug reaches systemic circulation [1], but it was not clarified whether the sulphoxidation look place in the liver, in the gut, or in both. That the ratio of the area under the levomepromazine curve to the area under the sulphoxide curve was larger for tablets than for syrup (Table 1) demonstrates that a larger fraction of the dose was converted to sulphoxide after administration of syrup than after tablets. Provided that sulphoxidation took place in the gut, the slightly larger extent of this process after administration of syrup may have been due to a higher initial concentration of levomepromazine in the gut shortly after administration of syrup than of tablets. Average plasma concentrations in 13 patients after repeated oral dosing with liquid, tablets and other dosage forms of chlorpromazine have previously been reported [5]. The area under the average plasma concentration curves from 1 h to 12 h after dosing divided by the dose was approximately 40% higher for oral liquid chlorpromazine than for chlorpromazine tablets. This might indicate that the congeners chlorpromazine and levomepromazine differ from each other with respect to the relative oral bioavailability of the drug in tablets and liquid preparations. This apparent difference, however, could just as well be due to differences in the pharmaceutical formulation of the chlorpromazine and levomepromazine tablets. In 6 of the 8 patients in the present study, the biological half-life of levomepromazine (Table 2) was within the range of previously reported values [1]. Both patients, 3 and 7, had a considerably longer

309 half-life of levomepromazine, but that of the sulphoxide did not show corresponding prolongation. It should be noted that determination of half-life of the sulphoxide was based on the assumption that it was only formed before the drug entered the general circulation. It can be seen from Table 1 that Patient 3, who eliminated levomepromazine at the lowest rate, was the oldest subject in the series. This is in accordance with previous reports that elderly people tend to have the highest plasma levels of thioridazine, probably due to a slower rate of metabolism [6, 7]. The individual variation in C1/Fpo may be due to variation in biological half-life, apparent volume of distribution and in the fraction of the administered dose reaching the systemic circulation as unchanged drug. The relatively low value of Cl/Fpo in Patient 3 (Table 2) was mainly due to slow metabolism of the drug in this subject. The highest values of C1/Fpo were in Patients 4 and 5. As shown by their biological half-life, these patients were not amongst the most rapid eliminators of levomepromazine, and their high values for Cl/Fpo may have been due, therefore, to low biological availabilities (Fpo). Patients 1 and 2 had previously been Subjects 1 and 2 in another study of the pharmacokinetics of chlorpromazine [4]. The values of C1/Fpo in these patients after 5 weeks of maintenance treatment with chlorpromazine tablets, 100mg × 2, were 70% and 96% larger, respectively, than the results found after maintenance therapy with levomepromazine tablets. This indicates that chlorpromazine tablets should produce plasma levels 35% to 50% lower than levomepromazine tablets given in the same doses. The levomepromazine doses had been adjusted to produce the optimal therapeutic outcome before each patient was asked if he would take part in the study. The results show that the patients who were treated with the largest doses (Patients 4, 5, and 6) also had the highest C1/Fpo values. Patient 3, on the other hand, who managed with the smallest dose in the series, had the lowest C1/Fpo value. These observations indicate that the individual variation in therapeutic dose was due in part to individual variation in the pharmacokinetics of the drug. The similarity of the plasma levels of levomepromazine, despite the great individual variation in therapeutic dose, suggests that there excists a therapeutic plasma concentration range for this drug.

Acknowledgements. This work was supported by grant B 0106.4033 from the Royal Norwegian Council for Scientific and Industrial Research, and by grants from the Norwegian Drug Monopoly, Anders

310

Jahre's Foundation for the Promotion of Science and from AB Leo, Helsingborg. The authors wish to thank the patients who volunteered to take part in this study. We are also indepted to Miss T. Morsund, Mrs. S. Ellefsen, E. Haug and E. Rystad for skilful technical assistance.

References 1. Dahl, S. G., Pharmacokirletics of methotrimeprazine after single and multiple doses. Clin. Pharmacol. Ther. 19, 435-442 (1976) 2. Dahl, S. G., Jacobsen, S.: GLC determination of methotrimeprazine and its sulfoxide in plasma. J. pharm. Sci. 65, 1329-1333 (1976) 3. Dahl, S. G., Refsum, H.: Effects of levomepromazine, chlorpromazine and their sulfoxides on isolated rat atria. Europ. J. Pharmacol. 37, 241-248 (1976) 4. Dahl, S. G., Strandjord, R. E.: Pharmacokinetics of chlorpromazine after single and multiple doses. Clin. Pharmacol. Ther. In press

S. G. Dahl et al.: Pharmacokinetics of Levomepromazine 5. Hollister, L. E., Curry, S. H., Derr, Julia E., Kanter, S. L.: Studies of delayed-action medication. V. Plasma levels and urinary excretion of four different dosage forms. Clin. Pharmacol. Ther. 11, 49-59 (1970) 6. Klein, H. E., Chandra, O., Matussek, N.: Therapeutische Wirkung und Plasmaspiegel von Thioridazin (Melleril) bei schizophrenen Patienten. Pharmacopsych. 8, 122-131 (1975) 7. M~rtensson, E., Roos, B.-E.: Serum levels of thioridazine in psychiatric patients and healthy volunteers. Europ. J. clin. Pharmacol. 6, 181-186 (1973) 8. Riegelman, S., Loo, J., Rowland, M.: Concept of a volume of distribution and possible errors in evaluation of this parameter. J. pharm. Sci. 57, 128-133 (t968) Received; June 2, 1976 and in revised form: August 30, 1976, accepted: November 11, 1976 Dr. S. G. Dahl Institute of Medical Biology University of Tromso N-9001 Tromso Norway

Pharmacokinetics and relative bioavailability of levomepromazine after repeated administration of tablets and syrup.

European Journal of Clinical Pharmacology Europ. J. clin. Pharmacot. 11,305-310 (1977) © by Springer-Vcrlag 1977 Pharmacokinetics and Relative Bioa...
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