Pharmacokinetics of methotrimeprazine after single and multiple doses Concentrations of methotrimeprazine and a metabolite, methotrimeprazine sulfoxide, were measured in plasma after a single intramuscular dose and after single and multiple oral doses of methotrimeprazine. The highest plasma concentrations of methotrimeprazine were found 30 to 90 min after intramuscular injection, and 1 to 3 hr after oral administration. On average 50% of orally administered drug reached the general circulation as unchanged methotrimeprazine. The apparent volume of distribution (V 13) was 23 to 42 Llkg body weight, and the biologic half-life, 15 to 30 hr. The sulfoxide could not be traced in plasma after a 25-mg intramuscular dose, but was found in higher plasma concentrations than the unmetabolized drug after single and multiple oral doses. This could be due to oxidation of the drug either in the gastrointestinal lumen or in the intestinal wall, or during its first passage through the liver. The apparent half-life of the sulfoxide was on average 30 % shorter than the half-life of methotrimeprazine.
Svein G. Dahl, Ph.D. Oslo, Norway Institute of Pharmacology, University of Oslo
The phenothiazine congener, methotrimeprazine, was introduced by Rh6ne-Poulenc in 1958, and has since been widely used in Europe under the name levomepromazine as a neuroleptic with pronounced sedative effect. In the United States the drug is used as an analgesic. It has several effects similar to chlorpromazine, but perhaps a stronger tendency to give orthostatic hypotension. 4 , 10 The disposition of methotrimeprazine has been studied in mice 1 and in rats,2 but scant
Supported by Grant No. B0106.4033 from the Royal Norwegian Council for Scientific and Industrial Research, and by grants from the Norwegian Drug Monopoly, the Scandinavian Society for Psychopharmacology, and the Godfred Lie Foundation. Received for publication Sept. 20, 1975. Accepted for publication Dec. 13, 1975. Reprint requests to: S. G. Dahl, Institute of Pharmacology, University of Oslo, P. O. Box 1057, Blindern, Oslo 3, Norway.
information is available about its kinetics in man. Like other phenothiazines, it may theoretically be converted in the body to a large number of metabolites, but only three have yet been identified and quantitated in human urine. 8 One of these, methotrimeprazine sulfoxide, appeared in considerably higher concentrations than the other two metabolites in urine from 3 psychiatric patients who had taken the drug orally. It was later reported that plasma from 3 psychiatric patients treated with methotrimeprazine orally for several weeks contained higher concentrations of the sulfoxide than of the parent drug. 6 This study was undertaken in order to obtain more complete information on the pharmacokinetics of methotrimeprazine in man, and as an attempt to discover the reason for the apparently high plasma levels of the sulfoxide. 435
Special abbreviations used A area under plasma concentration curves total area under the plasma concentration curve after a single dose, from zero time and until the drug has completely disappeared again from plasma area under the plasma concentration AO-T curve after a single dose, from zero to time T area under the plasma concentration curve in one dosage interval, which was 12 hr, at steady-state apparent rate constant in the terminal f3 exponential phase total clearance last plasma concentration, measured at time T after a single dose administered dose biologic availability fraction of intramuscularly administered dose reaching systemic circulation as unchanged drug fraction of oraIIy administered dose reaching systemic circulation as unchanged drug methotrimeprazine LM LMSO methotrimeprazine sulfoxide SD standard deviation biologic half-life tt apparent volume of distribution Vf3 Methods
Subjects. Five male psychiatric patients, 58 to 63 yr of age, volunteered to take part. They had all been in a psychiatric hospital for several years, and had previously been treated with various neuroleptics, including methotrimeprazine. Three of the patients had been without any medication for 2 mo before the study was initiated, 1 received methotrimeprazine tablets, 150 mg per day, and 1 received clopenthixol tablets, 20 mg per day. The patients were somatically healthy, with normal ECG, hemoglobin, serum creatinine, alkaline phosphatases, bilirubin, serum proteins, and serum cholesterol, both before and after the study. Experimental design. The patients received no drugs for 4 wk prior to the study, and no drugs except methotrimeprazine were given during the study. Methotrimeprazine was given orally as syrup, together with a meal of sand-
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wiches, milk, and coffee, according to the hospital routine. The syrup and the solution for injection contained methotrimeprazine HCI, but the doses are given here as the equivalent amount of the base. The methotrimeprazine syrup was analyzed after dilution by the same assay as the plasma. The concentration of methotrimeprazine sulfoxide was 0.8 % of that of methotrimeprazine. Each series of blood sampling started with a sample immediately before the drug was administered (0 hr). Single oral dose. The study started with a single oral dose of 50 mg. Blood samples were collected for 12 or 24 hr by the following scheme: 0, 1,2,3,4,5,6,8, 12, and 24 hr. Single intramuscular dose. A single dose of 25 mg was injected into the left gluteal area, and the patient kept recumbent for the next hour to prevent orthostatic hypotension. Blood samples were collected after 0, V2, 1, 1V2, 2, 3, 4, 6, 8, 12,24, and 36 hr. Patients 1 and 2 were given the intramuscular dose 6 mo after termination of oral dosing with methotrimeprazine. They had received no drugs in the meantime. Patients 4 and 5 received the intramuscular dose 2 wk after the single oral dose, before oral maintenance dosing was started. Patient 3 had a transient attack of orthostatic hypotension after the single oral dose, and was therefore not given an intramuscular dose. Repeated oral dosing. Oral maintenance doses were given for 21 days. Patient 3 received 25 mg twice daily and the others received 50 mg twice daily. Blood samples were collected within one dosage interval (12 hr) on the seventh day, and for 24 to 48 hr after the last maintenance dose, by the following scheme: 0,1,2,3,4,5,6,8,12,24,36, and 48 hr. Blood sampling and assay procedure. Five or 10 ml of blood were collected in heparinized polyethylene tubes, from a cubital vein. An indwelling cannula was used for the first nine samples of each series, which were taken during one day. Upon immediate centrifugation, two aliquots of plasma were transferred to polystyrol tubes, frozen, and kept at -24 0 C. The plasma concentrations of methotrimeprazine and methotrimeprazine sulfoxide were
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25 mg Lm. n =4
Fig. 1. Average plasma concentrations of methotrimeprazine, given as ng base per ml, after a 25-mg intramuscular dose. The triangles and vertical bars represent mean values from 4 patients and standard error of the mean, respectively.
determined by a gas chromatographic method. 6 The two aliquots from the same plasma sample were analyzed on two different days, within 6 wk. P harmacokinetic calculations. Pharmacokinetic constants were calculated for each patient, assuming: (1) first-order kinetics for elimination of methotrimeprazine and (2) tt, V , F im , and Fpo independent of drug concentrations and constant for each patient during the study. The areas under the observed plasma concentration curves were calculated by the trapezoidal rule. The total area under the curves after single intramuscular and oral doses were calculated by the equation Ao-oo = AO-T
CT' t, In2
deviation of tt could not be estimated for Patient 1, where only 2 points on the plasma concentration-time curve were obtained in the postdistribution phase. The apparent volume of distribution 12 for methotrimeprazine divided by Fim , was calculated from the biologic half-life and the total area under the curve after the intramuscular injection, by the equation Vf3/Fim = A
D . t, 0-00
Equation 2 was derived from the area equationl8, 19: (3)
assuming that the last plasma concentration (C T ) was measured at pseudodistribution equilibrium. 12 Estimates for the biologic half-lives and standard deviation of the estimates were calculated for each patient by linear regression analysis. The slope of the least-squares regression line and its standard deviation were calculated from the logarithms of the 3 or 4 plasma concentrations measured 12 to 48 hr after the last maintenance dose. The standard
where /3 = 1tiln 2. The total clearance of the drug, relative to Rm, was calculated from the total areas under the curves after intramuscular injections, by the equation 18: CI = Fim . D Ao-oo D CI/Fim = - A
The ratio of the biologic availabilities by oral and intra~uscular administration was calcu-
Clinical Pharmacology and Therapeutics
PATIENT 1 _elM 0-0 LMSO