PHARMACOKINETICS OF DROPERIDOL IN SURGICAL PATIENTS UNDER DIFFERENT CONDITIONS OF ANAESTHESIA

Br. J. Anaesth. (1988), 61, 297-301

PHARMACOKINETICS OF DROPERIDOL IN SURGICAL PATIENTS UNDER DIFFERENT CONDITIONS OF ANAESTHESIA K. A. LEHMANN, A. VAN PEER, M. IKONOMAKIS, R. GASPARINI AND J. HEYKANTS

KLAUS A. LEHMANN,

PH.D., M.D. ; MICHAEL

IKONOMAKIS,

M.D.; Department of Anaesthesiology, University of Koln, Joseph-Stelzmann-Strasse 9, D-5000 Koln 41, Germany. ROLAND GASPARINI, CHEM.ENG. ; ACHIEL VAN PEER, PH.D. ; Jos

HEYKANTS, PH.D.; Department of Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium. Accepted for Publication: December 11, 1986.

SUMMARY The pharmacokinetics of droperidol were studied in 42 surgical patients using doses of 5, 10 and 15mg i.v.. in association with neuroleptanalgesia or volatile anaesthetics. Plasma concentrations of droperidol were measured by radioimmunoassay. During neuroleptanalgesia, droperidol kinetics were linear over the dose range tested: the overall mean elimination ha/flife was 127 min, \ldss 103 litre and the plasma clearance 732 ml min''. The kinetics of droperidol were similar under neuroleptanalgesia and under anaesthesia with halothane or enflurane. There was no significant correlation between the volume of distribution or clearance with age (14-65 yr) or body weight (48-90 kg).

PATIENTS AND METHODS

Forty-two patients (ASA grades I—II) scheduled to undergo elective abdominal, gynaecological or orthopaedic surgery participated after giving informed consent. Duration of surgery was at least 60 min. None of the patients had any significant hepatic or renal impairment. Individuals addicted to alcohol or drugs were excluded. All patients were premedicated with diazepam 10 mg by mouth on the evening before surgery and 10 mg i.m. 1 h before surgery. Atropine 0.5 mg i.v. was followed by alcuronium 2 mg, diazepam 5 mg, hexobarbitone 3 mg kg"1 and 50 % nitrous oxide in oxygen for 2—3 min. Suxamethonium 1 mg kg"1 was used to facilitate tracheal intubation. Patients were randomly assigned tofivegroups. Patients of groups 1,2 and 3 received a single dose of droperidol 5, 10 and 15 mg i.v. respectively,

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Droperidol is a butyrophenone with neuroleptic properties used to supplement anaesthesia. It has pronounced antiemetic effects. Droperidol is often combined with volatile anaesthetics during balanced anaesthesia, or with the potent narcotic analgesics fentanyl or alfentanil in neuroleptanalgesia. Data on the pharmacokinetics of droperidol in man are scarce. Cressman, Plostnieks and Johnson [1], performed a preliminary pharmacokinetic study in healthy, non-anaesthetized volunteers after an i.v. dose of 5 mg of 3H-labelled droperidol. They determined the concentrations of droperidol by a radioassay after thin-layer chromatographic separation of droperidol. An elimination half-life of 134 min was obtained but no values of the clearance or the volumes of distribution were reported. More recently, Fischler and colleagues [2] studied the kinetics of droperidol using a specific radioimmunoassay method after an i.v. bolus injection of 150 (ig kg"1 in 10 anaesthetized patients. In the present study, the knowledge on the pharmacokinetics of droperidol was extended. The linearity of the kinetics of droperidol i.v. was determined using doses of 5, 10 and 15 mg, and the possibility that volatile anaesthetics alter the kinetics of droperidol was also investigated. Because of the large patient population included, age and body weight were studied as possible factors influencing the variation in droperidol disposition.

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TABLE I. Values of C, and X, in the bi- and triexponential equations fitting the individual droperidol plasma concentrations

C2

Patient

No.

(ng ml-1)

(ng ml l )

(min"1)

;.2 (min-1)

;-3 (min-1)

375 361 1626 66 151 505 84 451 329 251

40 47 73 27 22 24 68 40 40 37

— — 36 — — 14 — 31 — —

0.527 0.243 0.45 0.254 0.119 0.48 0.165 0.32 0.198 0.248

0.0086 0.0068 0.051 0.0050 0.0053 0.037 0.0067 0.035 0.0062 0.0054

— — 0.0068 — — 0.0024 — 0.0053 — —

950 1276 11232 770 1967 918 351 116 436 470

106 81 179 115 132 148 116 30 97 63

29 49 70 65 — 71 — — — 49

0.66 0.68 0.89 0.27 0.282 0.74 0.149 0.139 0.345 0.41

0.021 0.039 0.071 0.035 0.0080 0.088 0.0078 0.0061 0.0071 0.024

0.0036 0.0049 0.0071 0.0041 — 0.0064 — — — 0.0040

489 271 2668 2244 257 360 2607 176 252 345

128 92 112 121 127 139 125 107 143 70

— — 62 — — — 98 — — —

0.158 0.070 0.59 0.319 0.099 0.290 1.04 0.242 0.204 0.525

0.0067 0.0050 0.025 0.0055 0.0072 0.0071 0.081 0.0065 0.0068 0.0093

— — 0.0053 — — — 0.0057 — — —

548 1700 1598 262 619 3611

332 67 94 54 80 134

45 29 33 28 22 44

0.40 0.79 1.17 0.79 0.66 0.94

0.040 0.050 0.045 0.040 0.023 0.054

0.0044 0.0050 0.0051 0.0042 0.0040 0.0056

434 118 2054 1016 518 1074

73 68 44 71 67 80

— — 34 40 31 25

0.224 0.067 1.07 0.83 0.33 0.90

0.0072 0.0076 0.052 0.065 0.040 0.032

— — 0.0052 0.0065 0.0043 0.0046

together with fentanyl 4 ng kg"1 i.v. Artificial ventilation with a mixture of 60 % nitrous oxide in oxygen was used. Supplementary doses of fentanyl 0.1-0.2 mg and alcuronium 3 mg were added when necessary. Patient groups 4 and 5 received droperidol 10 mg i.v. only but, initially,

ventilation was with volatile anaesthetics: 1.5 vol % halothane or 2 vol % enflurane in nitrous oxide—oxygen. Ten minutes later, the halothane and enflurane concentrations were reduced to 1 and 1.5 vol %, respectively. Heparinized 3-ml venous blood samples were drawn from the

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Droperidol 5 m g 1 2 3 4 5 6 7 8 9 10 Droperidol 10 m g 1 2 3 4 5 6 7 8 9 10 Droperidol 15 m g 1 2 3 4 5 6 7 8 9 10 Halothane 1 2 3 4 5 6 Enflurane 1 2 3 4 5 6

c3

(ng ml-')

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contralateral arm in all patients, before administration of drugs and at 1, 3, 6, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after administration. Blood samples were centrifuged and plasma was stored at — 20 °C until required for assay. Radioimmunoassay

Pharmacokinetic and statistical analysis

Plasma concentration-time data were fitted to a bi- or triexponential equation (table I): C = £ Cfi-* Initial estimates of the parameters C, and 1{ were obtained with the method of residuals [3]. Final estimates were calculated by the non-linear leastsquares regression program of SAS [4] with the Marquardt algorithm and weighting by the inverse square of the plasma concentration. The goodness of fit was judged by the F ratio test [5], standard deviations on parameters and scatter diagrams of the residuals between measured and predicted plasma concentrations. Plasma clearance (C7), volumes of distribution (Fd ss , Fdarea), half-lives (7J) and mean residence times (MRT) were calculated by standard methods [3]. Analysis of variance [4] was applied to Fdss, Kdarea, Cl, MRT andTj to test for differences in these parameters over the studied dose range and effects of anaesthetics. The least significant difference test was used to compare pairs of means. All tests were two-tailed. Statistical significance was

120

180

240

300

360

Time (min) FIG. 1. Mean (SEM) droperidol plasma concentrations after i.v. administration of 5, 10 and 15 mg to surgical patients under neuroleptanalgesia. Expressions describing the time courses of the mean droperidol plasma concentrations were: c = 697e-°-64' + 41.5e- OO28 ' + 26.5e- 0 0 0 4 " (5 mg); c = 661e-° 3 °' + 73.1e-° O25' + 56.2e-° 0053 ' (10 mg); c = 853e-°-38l + 83.2e- 0 0 3 " + 87.0e- 0 0 0 5 3 ' (15 mg).

declared at P < 0.05. Linear regression was performed to determine if there was any relationship between the pharmacokinetic parameters of droperidol and the factors age and body weight. All results are expressed as mean (SD). RESULTS

After i.v. administration of droperidol its plasma concentrations decreased rapidly during the first 15 min (fig. 1). Following the distribution phase, concentrations decreased in parallel for the three doses. Plasma concentration-time profiles in some individuals were best characterized by a biexponential equation, whereas a triexponential model fitted the data more closely in others. The modelindependent kinetic parameters in the neuroleptanalgesia groups are shown in table II. There

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Droperidol plasma concentrations were measured by a radioimmunoassay kit for benperidol (Janssen Life Sciences Products, Beerse, Belgium), because of the better radiochemical stability of 3H-benperidol. The assay can be used for the determination of droperidol because of the favourable cross-reaction between both analogues, and metabolites of droperidol do not interfere. The method has been described in detail in the Appendix of the paper by Fischler and colleagues [2]. All plasma samples were measured in duplicate. Intra-assay variability between duplicates was 2.8 (0.1)%. Inter-assay variation was 12.3% and 13.9 % for droperidol concentrations of 10 ng ml"1 and 1 ng ml"1, respectively. Specific and nonspecific binding were 44.2 (0.9) % and 1.9 (0.3) %, respectively.

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TABLE II. Model-independent pharmacokinetic parameters of droperidol 5, 10 and 15 mg i.v. under neuroleplanalgesia

Patient

SD

(min)

70 62 70 70 57 68 58 68 55 70 65 6

94 73 38 169 135 216 67 81 80 103 106 53

108 88 71 177 174 277 70 112 99 118 129 64

932 595 483 883 923 664 469 595 616 636 680 173

101 122 79 191 146 325 142 136 129 162 153 68

81 102 102 139 131 289 103 131 112 128 132 58

38 61 46 57 . 23 56 34 31 22 60 43 15

70 90 78 83 48 86 74 52 74 77 73 14

117 108 23 82 38 89 65 245 87 124 98 61

191 146 56 111 53 111 74 285 94 156 128 71

688 717 400 455 426 713 580 1738 670 624 701 384

171 150 58 181 89 125 112 141 129 198 135 43

193 141 98 169 87 108 89 114 98 173 127 39

36 44 54 53 17 34 57 72 14 65 45 19

70 80 70 55 60 69 67 48 58 75 65 10

87 113 84 72 91 96 101 129 94 182 105 31

101 135 137 94 103 101 124 134 99 197 123 31

676 674 725 517 741 721 706 873 674 1833 814 368

129 168 116 139 122 133 143 148 139 99 134 19

103 139 131 126 96 98 122 107 102 75 110 19

M F F F F M F F M F

28 59 54 57 61 62 53 44 37 43 50 11

M M M F F F F F F F

F M F F F M M M F F

SD Droperidol 15 m g 21 22 23 24 25 26 27 28 29 30 Mean

MRT (min)

were no significant differences between the pharmacokinetic parameters at the different doses. Combination of the 5-, 10- and 15-mg data (n = 30) produced a pooled mean elimination half-life of 127 + 37 min, a plasma clearance of 798(39) ml min"1 and volumes of distribution of 111 (50) litre (Fd ss ) and 145 (64) litre (Kdarea). Volumes of distribution and clearance values were not dependent on age or body weight, as indicated by the low correlation coefficients (r2 < 0.13). Concomitant use of volatile anaesthetics did not significantly alter droperidol volumes of distribution and clearance (table III).

DISCUSSION

The present study demonstrated the linearity, or dose-independence, of the kinetics of droperidol after single i.v. administration of 5, 10 and 15 mg—three droperidol doses in the therapeutic range. The similarity of the mean droperidol plasma concentration-time curves at each of the doses suggests that the kinetics do not change as the dose increases. The insignificant differences in volumes of distribution and clearance confirm this independence of dose. Furthermore, the half-life did not change as a function of dose. The kinetic

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Droperidol 5 m g 1 2 3 4 5 6 7 8 9 10 Mean SD Droperidol 10 m g 11 12 13 14 15 16 17 18 19 20 Mean

n

(ml min" 1 )

Weight (kg)

Sex

a

(litre)

Kd"re» (litre)

Age (yr)

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TABLE III. Model-independent pharmacokinetic parameters of droperidol 10 mg under volatile anaesthesia

Patient

Weight (kg)

Kd 55 (litre)

yd*"* (litre)

(ml min" 1 )

a

MRT (min)

T i (min)

M M M M M M

15 52 35 29 26 42 33 13

100 73 68 73 85 65 77 13

64 138 134 233 155 72 133 62

114 215 198 285 252 126 198 68

503 1076 1008 1198 1008 705 916 260

127 128 133 194 154 102 140 31

158 139 136 165 173 124 149 19

M M M F M F

21 24 61 36 36 47 38 15

75 85 70 60 73 60 71 10

97 105 147 135 158 151 132 25

115 123 207 182 222 238 181 52

828 934 1075 1181 957 1096 1012 128

117 112 137 114 165 138 131 20

96 91 133 107 161 151 123 29

parameters obtained in this study were very similar to those previously reported by Fischler and colleagues [2]. In contrast to the present study, they determined the kinetics of droperidol at only one dose—150 |ig kg"1, corresponding to a 10-mg total dose. The volatile anaesthetics halothane and enflurane did not significantly affect the kinetics of droperidol, probably because interindividual variability existed under each condition of anaesthesia. The clearance of droperidol 10 mg ranged from 400 to 1738 ml min"1 in neuroleptanalgesia, from 503 to 1198 ml min"1 in the halothane group and from 828 to 1181 ml min"1 in the enflurane group. Thus the ranges of clearances do not appear to differ. The same considerations are relevant to the volumes of distribution and halflives. Normalizing the clearance and volumes of distribution for body weight did not decrease the interindividual variability. Coefficients of variation on weight-normalized parameters were as large as for the uncorrected parameters. Clearance and volumes of distribution were also not influenced by age, at least in the range 14-65 yr.

In conclusion, droperidol i.v. in three therapeutic doses exhibited dose-linear kinetics under neuroleptanalgesia, and the kinetics were not greatly influenced by volatile anaesthetics. Further, the present study indicated that age and body weight of the normal population of adult surgical patients had no clinically relevant influence on the kinetics of droperidol.

REFERENCES 1. Cressman WA, Plostnieks J, Johnson PC. Absorption, metabolism and excretion of droperidol by human subjects following intramuscular and intravenous administration. Anesthesiology 1973; 38: 363-369. 2. Fischler M, Bonnet F, Trang H, Jacob L, Levron JC, Flaisler B, Vourc'h G. The pharmacokinetics of droperidol in anesthetized patients. Anesthesiology 1986; 64: 486-489. 3. Gibaldi M, Perrier D. Pharmacokinetics. 2nd Edn. New York: Marcel Dekker, 1982; 409-417, 433-444. 4. SAS User's Guide Statistics. Cary: SAS Institute Inc., 1985. 5. Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimations in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1974; 2: 123-148.

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Halothane 31 32 33 34 35 36 Mean SD Enflurane 37 38 39 40 41 42 Mean SD

Age (yr)

Sex