Br.J. Anaesth. (1976), 48, 643
PHARMACOKINETICS OF METHOHEXITONE FOLLOWING INTRAVENOUS INFUSION IN HUMANS D. D. BREIMER SUMMARY
Methohexitone (a-dl-1 methyl-5 (1 methyl-2 pentynyl) 5 allyl-barbituric acid) is an ultrashort-acting barbiturate, which is frequently used as an i.v. anaesthetic (Whitwam, 1972). It is approximately three times as potent as thiopentone (Thomas, 1967; Clarke et al., 1968) and recovery from anaesthesia was reported to be significantly shorter than after thiopentone (Egbert, Oech and Eckenhoff, 1959; Elliott et al., 1962; Barry, Lawson and Davidson, 1967). As a consequence the management of ambulatory patients can be simplified and their stay in hospital can be shortened safely (Barlow and Gottlich, 1962; Whitwam, 1972). These clinical findings indicate that methohexitone may be relatively rapidly inactivated in man, either by biotransformation or by sequestration in body fat. Brand and others (1963) have studied plasma and adipose tissue concentrations in humans following the administration of exceptionally high doses of at least 1200 mg. Their results indicated that the elimination rate of methohexitone from plasma was faster than that of thiopentone. However, definite conclusions could not be drawn since concentrations could be measured only up to 5 h, because of the limited sensitivity of their u.v. assay method. Sunshine and others (1966) developed a gas chromatographic method to measure blood concentrations after clinical doses (1.5-2 mg/kg), but the sensitivity of their procedure did not allow the measurement of drug concentrations for more than
10 min following i.v. injection. For the present investigation improvements were made in the sensitivity of the assay to methohexitone, using gas chromatography with a nitrogen selective detector. This now makes it feasible to study the pharmacokinetics after therapeutic doses in man. METHODS
Assay of methohexitone in plasma Extraction procedure. To 2.0 ml plasma 2 ml of distilled water was added together with 0.10 ml of an internal standard solution containing hexobarbitone 3.0 |j.g. After homogenization, the mixture was extracted twice for 5-10 s with 10 ml of a mixture of light petroleum (b.p. 40-60 °C) and amyl alcohol in a ratio of 100: 2 on a whirlmixer. The organic solvent layers were transferred to a conical tube and evaporated to dryness. The residue was dissolved in 0.1 ml absolute ethanol and 2-5 [ilitre of this solution was injected into the gas chromatograph. Gas chromatography. A Hewlett-Packard, Model 5750 gas chromatograph, equipped with a nitrogen detector (rubidium bromide; HP 15161 A), was used. (Column: 230°; injection port: 280°; detector: 380°. Gas flow-rates: carrier (helium) 25 ml/min; auxiliary carrier to the nitrogen detector in order to obtain optimal performance 25 ml/min; hydrogen 30 ± 0.5 ml/min; air 200 ml/min.) A typical chromatogram is shown in figure 1. Preparation of calibration graphs. The concentraD. D. BREIMER, PH.D., Department of Pharmacology, tions of methohexitone in plasma were calculated Subfaculty of Pharmacy, University of Leiden, P.O. Box with the aid of calibration graphs, which were 722, Leiden, The Netherlands.
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A sensitive method, using gas chromatography with nitrogen selective detection, has been developed for the accurate measurement of methohexitone, in plasma, in concentrations of less than 0.05 (ig/ml, and which makes it possible to study the pharmacokinetics of the drug after clinical doses in man. Methohexitone sodium 3.0 mg/kg was administered by zero-order infusion to healthy volunteers and plasma concentrations were measured during and after infusion. The decrease in the plasma concentration of methohexitone can be described by two-compartment kinetics. The terminal elimination half-life of the drug is relatively short (70-125 min), which is a result of a high metabolic clearance rate (657-999 ml plasma/min). It was concluded that uptake of the drug by adipose tissue does not contribute significantly to its pharmacokinetics in man. In addition to the initial redistribution of an anaesthetic dose of methohexitone, the quick recovery of patients is a result of rapid metabolism of the drug.
644
BRITISH JOURNAL OF ANAESTHESIA m
2.5 n
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time (min) FIG. 1. Gas chromatogram of a 2-ml plasma extract obtained from a patient 10 min after receiving methohexitone sodium 200 mg by rapid i.v. injection, m = methohexitone (plasma concentration: 3.8 ng/ml); h = hexobarbitone (internal standard: plasma concentration 1.50 ng/ml), which was added to the plasma sample before extraction. The methohexitone concentration was calculated from the peak area ratio methohexitone/hexobarbitone with the aid of a calibration graph (fig. 2).
prepared by adding known amounts of methohexitone to 2.0 ml of blank plasma. The samples were analysed by the same procedure as described above and the ratio of the peak area of methohexitone to the internal standard was plotted against known concentrations of methohexitone (fig. 2). Volunteers and experimental procedure
Methohexitone sodium for i.v. injection was obtained from Messrs E. Lilly (U.S.A.). Solutions for i.v. infusion were prepared, immediately before use, by dissolving the sterile contents of a sealed container in sterile saline (10 mg/ml). Four healthy male volunteers, ranging in age from 23 to 27 years and in body weight from 55 to 81 kg,
0.5 1 1 5 Hg methohexitone/ ml plasma FIG. 2. Calibration graph for the gas chromatographic determination of methohexitone in plasma, using hexobarbitone as internal standard. The curve was obtained by adding known amounts of methohexitone to 2-ml plasma samples containing a fixed amount of internal standard (1.50 ng/ml) and by determining the experimental gas chromatographic peak area ratio of the two compounds.
who had given full consent, participated in the study. They had received no regular medication during the 4 weeks preceding the experiments. After an overnight fast, the volunteers received methohexitone sodium i.v. in doses of 3.0 mg/kg, by a 60-min zeroorder infusion (constant infusion rate of 0.05 mg/kg/ min). To minimize cardiorespiratory depression and to prevent too deep a level of narcosis, a relatively slow infusion procedure for i.v. drug administration was preferred. The volunteers rested supine during the infusion and for 3 h after infusion. Blood samples were taken from a forearm vein at the following times during infusion: 10, 20, 30, 40, 50 and 60 min. After infusion blood samples were taken usually after 5, 10, 15, 25, 35, 45, 55, 75, 95 min and after 2, 3, 4, 5 and 6 or 7 h. The blood was heparinized and centrifuged,
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xu
PHARMACOKINETICS OF METHOHEXITONE and the plasma was separated and frozen until assayed. RESULTS
terminated. After this event, the plasma concentrationtime curve exhibited two distinct phases: an early phase with a relatively steep slope and a later phase with a more gradual slope (fig. 3). This suggests that the early rapid reduction in the plasma concentration of methohexitone is dictated by rapid tissue localization, whereas the subsequent more gradual slope is a reflection of the elimination or sequestration of the drug. This behaviour is consistent with the concept that for methohexitone the body consists of two kinetically distinct compartments: a central compartment and a peripheral compartment (Riegelman, Loo and Rowland, 1968). The postinfusion plasma concentration curve can be represented mathematically as the sum of two exponentials according to Loo and Riegelman (1970): (1) where Cp (post) is the postinfusion plasma concentration, A\ and A\ are the coefficients (concentration intercepts of the exponential terms at t* = 0), a and /3 are the rate constants (reciprocal time constants), and t* is the time after the end of the infusion, that is t* = t— T, where T is the infusion time.
3.4
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330.00
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FIG. 3. Methohexitone plasma concentration curve (semi-logarithmic scale) during and after a 60-min zero-order i.v. infusion of methohexitone sodium into a healthy volunteer. The points (experimental concentrations) were fitted by non-linear least square regression analysis according to equations (2) and (5) (see text). The figure was obtained directly from a computer plot.
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The simple, rapid extraction procedure allows specific and sensitive gas chromatographic determination of methohexitone when using an alkali flame ionization detection system. Equally good results have been obtained previously for hexobarbitone by applying a procedure which is essentially the same as for methohexitone, using the latter as internal standard (Breimer and van Rossum, 1974a). The selectivity and sensitivity of the alkali flame ionization detector have made it possible to perform a quantitative assay of nitrogen-containing compounds in biological fluids, which has proved especially suitable for the study of the pharmacokinetics of barbiturates in humans (Breimer et al., 1975; Breimer and de Boer, 1975; Breimer and Winten, 1976). Linear calibration curves were obtained in the concentration range investigated (0.05-5.0 ji.g/ml plasma). During i.v. infusion of methohexitone sodium, a rapid increase in the methohexitone plasma concentration occurred until the zero-order infusion was
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BRITISH JOURNAL OF ANAESTHESIA
646 During infusion, the plasma concentration, based on two-compartment kinetics, can be described by the following equation: Cp =
(2)
.c
Clearance (Vcel), which is defined as the volume of plasma from which the drug is completely removed in unit time:
(3) V (4) Thus, for the postinfusion plasma concentration time course:
The distribution rate constants (&12 and &21) from the central to the peripheral compartment and vice versa: /C-i
.±
n — '
(5)
In the present investigation the concentrations during infusion were fitted according to equation (2) and the postinfusion concentrations were fitted according to equation (5), by using a non-linear curve-fitting program. The initial graphic estimates of a and £ were used as preliminary estimates. A weighting factor inversely proportional to the concentration was taken into account. An example of a fitted and directly plotted curve is given in figure 3 and it illustrates the agreement between the plasma concentrations and the two-compartment open model. In table I the fitted intercepts (A1 and A2) and the rate constants (a and /?) for the four volunteers are
These calculated parameters for methohexitone are given in table II. The half-life of the /3-phase varies from 70 to 125 min among the four volunteers. The average values for K^kg, F d /kg, Vcci, k12 and k21 are: 0.29 litre kg-1, 1.13 litre kg- 1 , 826 ml " * 0.056 min- 1 and 0.020 min- 1 respectively. DISCUSSION
The decrease in the plasma concentrations of methohexitone in human subjects following i.v. administration can be described by a two-compartment kinetic system. The mean a-value of 0.11 min"1
TABLE I. Fitted two-compartment open model parameters of methohexitone following i.v. infusion {relative standard errors in parentheses)
Subject H. K. 1
Aj (mg litre- ) A2 (mg litre' 1 ) a (min"1) P (min- 1 )
10.7 1.38 0.103 0.00725
(12.8%) (8.4%) (14.7%) (6.4%)
R. C. 9.87 0.74 0.102 0.00552
R. H.
(16.8%) 6.67 (13.3%) 1.11 (17.2%) 0.099 (12.8%) 0.00709
* Experimental parameters determined graphically by hand.
P. A.*
(34.9%) 7.50 (8.5%) 1.30 (25.4%) 0.139 (6.5%) 0.00990
Mean 8.69 1.13 0.111 0.00744
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where A1 and A2 are the hypothetical intercepts with the ordinate for an i.v. bolus injection of the same amount of drug (T is very short). It is evident that Ax and A2 are equal to A\ and A\ if T is very short, but the difference increases as the infusion time increase. The relationship between A\ and Ax and A\ and A2 is shown by the following equations (Loo and Riegelman, 1970):
given with their relative standard errors. Once these have been determined some important pharmacokinetic parameters intrinsic to a two-compartment open model may be calculated (van Rossum, 1971). The half-life (7^) of the /3-phase equals 0.69/£; the volume of the initial distribution space (Vt) equals D/(A1 + A2), whereas the steady state volume of distribution (F d ) can be calculated by the following equation:
PHARMACOKINETICS OF METHOHEXITONE
647
TABLE II. Experimental data and calculated pharmacokinetic parameters of methohexitone* Subject H. K. 23 74 204
2.76 60.0 95
0.23 0.87 692
9.35 0.051 0.018
25 55 152
2.76 60.0 125
0.26 1.30 657
11.95 0.049 0.012
R. H. 27 81 224
P. A. 24 64 177
2.76 60.0
2.76 60.0
97
70
0.35 1.25 999
12.33 0.051 0.020
0.31 1.10 955
14.93 0.072 0.029
Mean 24.8 68.5 189.3 2.76 60.0 97
0.29 1.13 826
12.14 0.056 0.020
* For explanation of symbols see text. t Dose (mg/kg) 2.76 mg of free acid = 3.0 mg of sodium salt.
suggests that distribution of the drag from plasma to tissues takes place very rapidly. For a highly lipophilic drug such as methohexitone, the slower /?phase may be a result of elimination by metabolism, sequestration by fat, or a combination of these processes. It has been shown for thiopentone that it is only after several hours that equilibrium is reached between the concentration in blood and in adipose tissue (Price et al., 1960). The return of the drag from tissues to blood then becomes a rate-determining step for elimination. Were the same sequence of events true for methohexitone, there would be a much slower decrease in the plasma concentrations of the drag which might be expected to show three phases (that is, to fit a three-compartment kinetic model). The concentrations in the present study 5 or 6 h after infusion were slightly higher than those corresponding to the fitted line of the £-phase. Therefore the fitting procedure was repeated on the assumption of a three-exponential equation underlying the plasma concentrations during and after infusion. A possible fit of the data to a three-compartment system was obtained in only two subjects, but there was a large variation in the fitted coefficients and rate constants. For the other two volunteers a three-compartment system could not be applied to the data. In support of the two-compartment hypothesis is the observation by Brand and others (1963) that methohexitone and hexobarbitone were less extensively localized in human fat than thiopentone. For hexobarbitone Breimer and colleagues (1975) have described the plasma concentration time course in humans, following i.v. infusion, by two-compart54
ment kinetics. If adipose tissue plays only a minor role in the elimination of methohexitone (and hexobarbitone) from human plasma, there is no reason to propose a three-compartment system for the elimination of these drugs. It may be derived from the high clearance constant for methohexitone (table II), that metabolism occurs so rapidly that substantial drug uptake by the poorly perfused fat tissue does not occur. Thus this is an important factor only at very high doses, and the plasma concentrations measured by Brand and others (1963) after i.v. infusion of methohexitone 1.2-1.8 g to four volunteers indicate that there may be a slower phase corresponding to a half-life of 3-5 h. However, they did not study plasma concentrations for a period sufficient to allow definite conclusions; moreover, the specificity of their u.v. assay method for unchanged drug is questionable. There remains the theoretical possibility of a more complex kinetic behaviour of methohexitone than that derived from the present experiments; it is used as a racemic mixture and, as in the case of hexobarbitone, the two enantiomers may differ in elimination rate (Breimer and van Rossum, 1973, 1974b). Sunshine and others (1966) found only small amounts of methohexitone in the urine and bile of man; less than 1% of the administered dose was excreted as unchanged methohexitone. Rapid metabelism seems to be the major reason for the high clearance value and the short half-life of the drug. The apparent volume of distribution is in the same order of magnitude as was found for hexobarbitone (Breimer et al., 1975). In support of the idea that methohexitone is metabolized rapidly is the fact that
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Age (yr) Body-weight (kg) Dose (mg free acid) Dose (kg/mg)f Infusion time (min) Half-life j3-phase (min) Kx/kg (litre) Kd/kg (litre) Clearance (ml min^1) Clearance/kg (ml min- 1 ) k12 (min-1) k21 (min-1)
R. C.
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BRITISH JOURNAL OF ANAESTHESIA
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Breimer, D. D., and de Boer, A. G. (1975). Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium in man after oral administration. Eur. J. Clin. Pharmacol., 9, 169. Honhoff, C , Zilly, W., Richter, E., and van Rossum, J. M. (1975). Pharmacokinetics of hexobarbital in man after intravenous infusion. J. Pharmacokin. Biopharm., 3, 1. van Rossum, J. M. (1973). Pharmacokinetics of ( + )-, ( —)- and ( + )-hexobarbital in man after oral administration. J. Pharm. Pharmacol., 25, 762. (1974a). Rapid and sensitive gas chromatographic determination of hexobarbital in plasma of man using a nitrogen detector. J. Chromatogr., 88, 235. (1974b). Pharmacokinetics of the enantiomers of hexobarbital studied in the same rat and in the same isolated perfused rat liver. Eur.J. Pharmacol., 26, 321. Winten, M. A. C. M. (1976). Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration. Eur. J. Clin. Pharmacol., 9, 443. Clarke, R. S. J., Dundee, J. W., Barron, D. W., and McArdle, L. (1968). Clinical studies of induction agents. XXVI: The relative potencies of thiopentone, methohexitone and propanidid. Br. J. Anaesth., 40, 593. Egbert, L. D., Oech, S. R., and Eckenhoff, J. E. (1959). Comparison of the recovery from methohexital and thiopental anesthesia in man. Surg. Gynecol. Obstet., 109, 427. Elliott, C. J. R., Green, R., Howells, T. H., and Long, H. A. (1962). Recovery from intravenous barbiturate anaesthesia: comparative study of recovery from methohexitone and thiopentone. Lancet, 2, 68. Gibaldi, M., Boyes, R. N., and Feldman, S. (1971). Influence of first-pass effect on availability of drugs on oral administration. J. Pharm. Sci., 60, 1338. ACKNOWLEDGEMENTS Loo, J. C. K., and Riegelman, S. (1970). Assessment of pharmacokinetic constants from postinfusion blood curves The experiments were carried out in the Department of obtained after i.v. infusion. J. Pharm. Sci., 59, 53. Pharmacology, University of Nijmegen, The Netherlands. The author wishes to thank Professor Dr J. M. van Rossum Price, H. L., Kovnat, P. J., Safer, J. N., Cormier, E. H., for valuable and stimulating discussions and Miss C. and Price, M. L. (1960). Uptake of thiopental by body Honhoff for her aid with the curve-fitting procedure. The tissues and its relation to the duration of narcosis. Clin. aid and medical supervision by Professor J. F. Crul and Pharmacol. Ther., 1, 16. Dr J. Duret, Department of Anaesthesiology, University of Riegelman, S., Loo, J. C. K., and Rowland, M. (1968). Nijmegen, are gratefully acknowledged. The excellent Shortcomings in pharmacokinetic analysis by conceiving technical assistance of Mrs C. P. W. G. M. Verweij-van the body to exhibit properties of a single compartment. Wissen in the determination of methohexitone plasma J. Pharm. Sci., 57, 117. concentrations is highly appreciated. van Rossum, J. M. (1971). Significance of pharmacokinetics for drug design and the planning of dosage regimens; in Drug Design (ed. E. J. Ariens), Vol. I, p. 469. New York: REFERENCES Academic Press. Barlow, M. B., and Gottlich, J. (1962). The use of metho- Rowland, M. (1972). Influence of route of administration on hexital to shorten safely the hospitalisation of day cases. drug availability. J. Pharm. Sci., 61, 70. Med. Proc, 8, 458. Sunshine, I., Whitwam, J. G., Fike, W., Finkle, B., and Barry, C. T., Lawson, R., and Davidson, D. G. D. (1967). Lebeau, J. (1966). Distribution and excretion of methoRecovery after methohexitone and thiopentone. Anaeshexitone in man. A study using gas and thin layer thesia, 22, 228. chromatography. Br. J. Anaesth., 38, 23. Brand, L.3 Mark, L. C , Snell, M. McM., Vrindten, P., and Thomas, E. T. (1967). The relative potencies of methoDayton, P. G. (1963). Physiologic disposition of methohexitone and thiopentone. Anaesthesia, 22, 16. hexital in man. Anesthesiology, 24, 331. Whitwam, J. G. (1972). The pharmacology of brietal Breimer, D. D. (1974).*Pharmacokinetics of hypnotic drugs. sodium (methohexitone sodium). Anaesthesiol. Wieder., Ph.D. Thesis, University of Nijmegen, The Netherlands. 57, 1.
the oral administration of methohexitone sodium results in low systemic bioavailability of the drug (Breimer, 1974). Apparently there is a substantial "first-pass" effect, which suggests that the compound is metabolized extensively during first passage through the liver after oral administration (Gibaldi, Boyes and Feldman, 1971; Rowland, 1972). It seems likely that methohexitone will be similar to thiopentone and hexobarbitone in its pattern of distribution immediately after i.v. injection. Rapid recovery of consciousness after a single i.v. dose of each of these drugs is largely a result of a redistribution process from the highly perfused viscera, including the central nervous system, into lean body mass (Price et al., 1960). In addition, it is highly probable that the rapid and complete recovery following methohexitone, as has been reported from many clinical observations (Whitwam, 1972), is a result of the rapid inactivation of the drug by metabolism. This should be considered of great benefit for operations of short duration. It may be mentioned that in the present experiments the volunteers experienced drowsiness and were generally inclined to fall asleep 15 min after the onset of infusion. Throughout the infusion period they could be awakened easily and, after termination of the infusion, recovery appeared to be complete within an hour, as judged by subjective rating.
PHARMACOKINETICS OF METHOHEXITONE PHARMACOCINETIQUE DU METHOHEXITONE APRES ADMINISTRATION INTRAVEINEUSE CHEZ LES HUMAINS RESUME
PHARMAKOKINETISCHE EIGENSCHAFTEN VON METHOHEXITON NACH DESSEN INTRAVENOSER VERABREICHUNG BEIM MENSCHEN ZUSAMMENFASSUNG
Eine sensitive Methode unter Verwendung von Gaschromatographie mit Stickstoff-Selektivfindung wurde entwickelt, um eine genaue Messung von MethohexitonPlasmakonzentrationen durchfuhren zu konnen, in Konzentrationen von weniger als 0,05 ng/ml; dadurch wird es moglich, die pharmakokinetischen Eigenschaften der Droge nach Verabreichung klinischer Dosen beim Men-
schen zu studieren. Methohexitonsodium (3,0 mg/kg) wurde intravenos an gesunde Versuchspersonen verabreicht, wobei wahrend und nach der Verabreichung die Plasmakonzentrationen gemessen wurden. Die Verringerung der Methohexiton-Plasmakonzentration kann durch zweiteilige Kinetik beschrieben werden. Die endgultige Ausscheidungs-Halbwertzeit der Droge ist relativ kurz (70-125 min) als Folge einer hohen metabolischen Ausscheidungsrate (657-999 Plasma/min). Zusammenfassend wurde festgestellt, dass die Aufnahme der Droge durch adipSses Gewebe nicht wesentlich zu ihren pharmakokinetischen Eigenschaften im Menschen beitragt. Zusatzlich zur anfanglichen Neuverteiliung einer narkotischen Dosis von Methohexiton ist die rasche Erholung von Patienten ein Ergebnis des rapiden Metabolismus der Droge. FARMACOCINETICA DE LA METOHEXITONA, CONSECUTIVA A INFUSION ENDOVENOSA EN EL HOMBRE SUMARIO
Un metodo sensitivo, usando cromatografia en fase gaseosa con detection selectiva de nitrogeno, ha sido desarrollado para la medicion exacta de metohexitona en el plasma, en concentraciones menores de 0,05 (J-g/ml, y que hace posible estudiar la farmacocinetica del farmaco tras dosis clinicas en el hombre. Se administro metohexitona sodica (3,0 mg/kg) mediante infusion orden-cero a voluntarios sanos, y se midieron las concentraciones plasmaticas durante y despues de la infusion. El descenso en la concentracion plasmatica de metohexitona puede ser descrito mediante cinetica duocompartamental. La media vida de eliminacion terminal del farmaco es relativamente breve (70 a 125 min), lo que es resultado de un elevado indice de aclaramiento metabolico (657 a 999 ml plasma/min). Se concluyo que la captaci6n del farmaco por el tejido adiposo no contribuye significativamente a su farmacocinetica en el hombre. Ademas de la redistribucion inicial de una dosis anest£sica de metohexitona, la recuperacion rapida de los pacientes es consecuencia del rapido metabolismo del farmaco.
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On a mis au point une technique tres precise basee sur la chromatographie en phase gazeuse avec detection selective de l'azote, pour mesurer les faibles concentrations de methohexitone dans le plasma, pour des concentrations inferieures a 0,05 Kg/ml, technique qui permet d'etudier la pharmacocinetique du medicament apres administration de doses cliniques a l'homme. On a administre en ordre zero des infusions de 3 mg/kg de methohexitone sodium a des volontaires en bonne same puis on en a mesure les concentrations dans le plasma pendant et apres l'infusion. La diminution de la concentration dans le plasma peut etre d£crite comme etant une cinetique a deux compartiments. La demi-vie terminale de l'elimination du medicament est relativement courte (70-125 min), et elle resulte du coefficient d'epuration plasmatique hautement metabolique (657-999 ml de plasma/min). On en a conclu que la fixation du medicament par les tissus adipeux ne contribue pas d'une maniere significative a sa pharmacocinetique chez l'homme. En plus de la redistribution initiale d'une dose anesthesiante de methohexitone, la recuperation rapide des patients resulte du m^tabolisme rapide du medicament.
649
PHARMACOKINETICS OF METHOHEXITONE FOLLOWING INTRAVENOUS INFUSION IN HUMANS D. D. BREIMER SUMMARY
Methohexitone (a-dl-1 methyl-5 (1 methyl-2 pentynyl) 5 allyl-barbituric acid) is an ultrashort-acting barbiturate, which is frequently used as an i.v. anaesthetic (Whitwam, 1972). It is approximately three times as potent as thiopentone (Thomas, 1967; Clarke et al., 1968) and recovery from anaesthesia was reported to be significantly shorter than after thiopentone (Egbert, Oech and Eckenhoff, 1959; Elliott et al., 1962; Barry, Lawson and Davidson, 1967). As a consequence the management of ambulatory patients can be simplified and their stay in hospital can be shortened safely (Barlow and Gottlich, 1962; Whitwam, 1972). These clinical findings indicate that methohexitone may be relatively rapidly inactivated in man, either by biotransformation or by sequestration in body fat. Brand and others (1963) have studied plasma and adipose tissue concentrations in humans following the administration of exceptionally high doses of at least 1200 mg. Their results indicated that the elimination rate of methohexitone from plasma was faster than that of thiopentone. However, definite conclusions could not be drawn since concentrations could be measured only up to 5 h, because of the limited sensitivity of their u.v. assay method. Sunshine and others (1966) developed a gas chromatographic method to measure blood concentrations after clinical doses (1.5-2 mg/kg), but the sensitivity of their procedure did not allow the measurement of drug concentrations for more than
10 min following i.v. injection. For the present investigation improvements were made in the sensitivity of the assay to methohexitone, using gas chromatography with a nitrogen selective detector. This now makes it feasible to study the pharmacokinetics after therapeutic doses in man. METHODS
Assay of methohexitone in plasma Extraction procedure. To 2.0 ml plasma 2 ml of distilled water was added together with 0.10 ml of an internal standard solution containing hexobarbitone 3.0 |j.g. After homogenization, the mixture was extracted twice for 5-10 s with 10 ml of a mixture of light petroleum (b.p. 40-60 °C) and amyl alcohol in a ratio of 100: 2 on a whirlmixer. The organic solvent layers were transferred to a conical tube and evaporated to dryness. The residue was dissolved in 0.1 ml absolute ethanol and 2-5 [ilitre of this solution was injected into the gas chromatograph. Gas chromatography. A Hewlett-Packard, Model 5750 gas chromatograph, equipped with a nitrogen detector (rubidium bromide; HP 15161 A), was used. (Column: 230°; injection port: 280°; detector: 380°. Gas flow-rates: carrier (helium) 25 ml/min; auxiliary carrier to the nitrogen detector in order to obtain optimal performance 25 ml/min; hydrogen 30 ± 0.5 ml/min; air 200 ml/min.) A typical chromatogram is shown in figure 1. Preparation of calibration graphs. The concentraD. D. BREIMER, PH.D., Department of Pharmacology, tions of methohexitone in plasma were calculated Subfaculty of Pharmacy, University of Leiden, P.O. Box with the aid of calibration graphs, which were 722, Leiden, The Netherlands.
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A sensitive method, using gas chromatography with nitrogen selective detection, has been developed for the accurate measurement of methohexitone, in plasma, in concentrations of less than 0.05 (ig/ml, and which makes it possible to study the pharmacokinetics of the drug after clinical doses in man. Methohexitone sodium 3.0 mg/kg was administered by zero-order infusion to healthy volunteers and plasma concentrations were measured during and after infusion. The decrease in the plasma concentration of methohexitone can be described by two-compartment kinetics. The terminal elimination half-life of the drug is relatively short (70-125 min), which is a result of a high metabolic clearance rate (657-999 ml plasma/min). It was concluded that uptake of the drug by adipose tissue does not contribute significantly to its pharmacokinetics in man. In addition to the initial redistribution of an anaesthetic dose of methohexitone, the quick recovery of patients is a result of rapid metabolism of the drug.
644
BRITISH JOURNAL OF ANAESTHESIA m
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±& 03
0.5-
time (min) FIG. 1. Gas chromatogram of a 2-ml plasma extract obtained from a patient 10 min after receiving methohexitone sodium 200 mg by rapid i.v. injection, m = methohexitone (plasma concentration: 3.8 ng/ml); h = hexobarbitone (internal standard: plasma concentration 1.50 ng/ml), which was added to the plasma sample before extraction. The methohexitone concentration was calculated from the peak area ratio methohexitone/hexobarbitone with the aid of a calibration graph (fig. 2).
prepared by adding known amounts of methohexitone to 2.0 ml of blank plasma. The samples were analysed by the same procedure as described above and the ratio of the peak area of methohexitone to the internal standard was plotted against known concentrations of methohexitone (fig. 2). Volunteers and experimental procedure
Methohexitone sodium for i.v. injection was obtained from Messrs E. Lilly (U.S.A.). Solutions for i.v. infusion were prepared, immediately before use, by dissolving the sterile contents of a sealed container in sterile saline (10 mg/ml). Four healthy male volunteers, ranging in age from 23 to 27 years and in body weight from 55 to 81 kg,
0.5 1 1 5 Hg methohexitone/ ml plasma FIG. 2. Calibration graph for the gas chromatographic determination of methohexitone in plasma, using hexobarbitone as internal standard. The curve was obtained by adding known amounts of methohexitone to 2-ml plasma samples containing a fixed amount of internal standard (1.50 ng/ml) and by determining the experimental gas chromatographic peak area ratio of the two compounds.
who had given full consent, participated in the study. They had received no regular medication during the 4 weeks preceding the experiments. After an overnight fast, the volunteers received methohexitone sodium i.v. in doses of 3.0 mg/kg, by a 60-min zeroorder infusion (constant infusion rate of 0.05 mg/kg/ min). To minimize cardiorespiratory depression and to prevent too deep a level of narcosis, a relatively slow infusion procedure for i.v. drug administration was preferred. The volunteers rested supine during the infusion and for 3 h after infusion. Blood samples were taken from a forearm vein at the following times during infusion: 10, 20, 30, 40, 50 and 60 min. After infusion blood samples were taken usually after 5, 10, 15, 25, 35, 45, 55, 75, 95 min and after 2, 3, 4, 5 and 6 or 7 h. The blood was heparinized and centrifuged,
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xu
PHARMACOKINETICS OF METHOHEXITONE and the plasma was separated and frozen until assayed. RESULTS
terminated. After this event, the plasma concentrationtime curve exhibited two distinct phases: an early phase with a relatively steep slope and a later phase with a more gradual slope (fig. 3). This suggests that the early rapid reduction in the plasma concentration of methohexitone is dictated by rapid tissue localization, whereas the subsequent more gradual slope is a reflection of the elimination or sequestration of the drug. This behaviour is consistent with the concept that for methohexitone the body consists of two kinetically distinct compartments: a central compartment and a peripheral compartment (Riegelman, Loo and Rowland, 1968). The postinfusion plasma concentration curve can be represented mathematically as the sum of two exponentials according to Loo and Riegelman (1970): (1) where Cp (post) is the postinfusion plasma concentration, A\ and A\ are the coefficients (concentration intercepts of the exponential terms at t* = 0), a and /3 are the rate constants (reciprocal time constants), and t* is the time after the end of the infusion, that is t* = t— T, where T is the infusion time.
3.4
Methohexitone sodium (3 MG/KG) Linear I.V. infusion 60 min Two compartment model
2.5 UJ 1.9
Subject H.K. 74 KG Healthy volunteer
1.3
O O H j
I
3" s z
O (
a.
u
8 ' 0.00
30.00
60.00
90.00
120.00
150.00
180.00
210.00
240.00
270.00
300.00
330.00
350.00
330.00
420.00
time (min)
FIG. 3. Methohexitone plasma concentration curve (semi-logarithmic scale) during and after a 60-min zero-order i.v. infusion of methohexitone sodium into a healthy volunteer. The points (experimental concentrations) were fitted by non-linear least square regression analysis according to equations (2) and (5) (see text). The figure was obtained directly from a computer plot.
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The simple, rapid extraction procedure allows specific and sensitive gas chromatographic determination of methohexitone when using an alkali flame ionization detection system. Equally good results have been obtained previously for hexobarbitone by applying a procedure which is essentially the same as for methohexitone, using the latter as internal standard (Breimer and van Rossum, 1974a). The selectivity and sensitivity of the alkali flame ionization detector have made it possible to perform a quantitative assay of nitrogen-containing compounds in biological fluids, which has proved especially suitable for the study of the pharmacokinetics of barbiturates in humans (Breimer et al., 1975; Breimer and de Boer, 1975; Breimer and Winten, 1976). Linear calibration curves were obtained in the concentration range investigated (0.05-5.0 ji.g/ml plasma). During i.v. infusion of methohexitone sodium, a rapid increase in the methohexitone plasma concentration occurred until the zero-order infusion was
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646 During infusion, the plasma concentration, based on two-compartment kinetics, can be described by the following equation: Cp =
(2)
.c
Clearance (Vcel), which is defined as the volume of plasma from which the drug is completely removed in unit time:
(3) V (4) Thus, for the postinfusion plasma concentration time course:
The distribution rate constants (&12 and &21) from the central to the peripheral compartment and vice versa: /C-i
.±
n — '
(5)
In the present investigation the concentrations during infusion were fitted according to equation (2) and the postinfusion concentrations were fitted according to equation (5), by using a non-linear curve-fitting program. The initial graphic estimates of a and £ were used as preliminary estimates. A weighting factor inversely proportional to the concentration was taken into account. An example of a fitted and directly plotted curve is given in figure 3 and it illustrates the agreement between the plasma concentrations and the two-compartment open model. In table I the fitted intercepts (A1 and A2) and the rate constants (a and /?) for the four volunteers are
These calculated parameters for methohexitone are given in table II. The half-life of the /3-phase varies from 70 to 125 min among the four volunteers. The average values for K^kg, F d /kg, Vcci, k12 and k21 are: 0.29 litre kg-1, 1.13 litre kg- 1 , 826 ml " * 0.056 min- 1 and 0.020 min- 1 respectively. DISCUSSION
The decrease in the plasma concentrations of methohexitone in human subjects following i.v. administration can be described by a two-compartment kinetic system. The mean a-value of 0.11 min"1
TABLE I. Fitted two-compartment open model parameters of methohexitone following i.v. infusion {relative standard errors in parentheses)
Subject H. K. 1
Aj (mg litre- ) A2 (mg litre' 1 ) a (min"1) P (min- 1 )
10.7 1.38 0.103 0.00725
(12.8%) (8.4%) (14.7%) (6.4%)
R. C. 9.87 0.74 0.102 0.00552
R. H.
(16.8%) 6.67 (13.3%) 1.11 (17.2%) 0.099 (12.8%) 0.00709
* Experimental parameters determined graphically by hand.
P. A.*
(34.9%) 7.50 (8.5%) 1.30 (25.4%) 0.139 (6.5%) 0.00990
Mean 8.69 1.13 0.111 0.00744
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where A1 and A2 are the hypothetical intercepts with the ordinate for an i.v. bolus injection of the same amount of drug (T is very short). It is evident that Ax and A2 are equal to A\ and A\ if T is very short, but the difference increases as the infusion time increase. The relationship between A\ and Ax and A\ and A2 is shown by the following equations (Loo and Riegelman, 1970):
given with their relative standard errors. Once these have been determined some important pharmacokinetic parameters intrinsic to a two-compartment open model may be calculated (van Rossum, 1971). The half-life (7^) of the /3-phase equals 0.69/£; the volume of the initial distribution space (Vt) equals D/(A1 + A2), whereas the steady state volume of distribution (F d ) can be calculated by the following equation:
PHARMACOKINETICS OF METHOHEXITONE
647
TABLE II. Experimental data and calculated pharmacokinetic parameters of methohexitone* Subject H. K. 23 74 204
2.76 60.0 95
0.23 0.87 692
9.35 0.051 0.018
25 55 152
2.76 60.0 125
0.26 1.30 657
11.95 0.049 0.012
R. H. 27 81 224
P. A. 24 64 177
2.76 60.0
2.76 60.0
97
70
0.35 1.25 999
12.33 0.051 0.020
0.31 1.10 955
14.93 0.072 0.029
Mean 24.8 68.5 189.3 2.76 60.0 97
0.29 1.13 826
12.14 0.056 0.020
* For explanation of symbols see text. t Dose (mg/kg) 2.76 mg of free acid = 3.0 mg of sodium salt.
suggests that distribution of the drag from plasma to tissues takes place very rapidly. For a highly lipophilic drug such as methohexitone, the slower /?phase may be a result of elimination by metabolism, sequestration by fat, or a combination of these processes. It has been shown for thiopentone that it is only after several hours that equilibrium is reached between the concentration in blood and in adipose tissue (Price et al., 1960). The return of the drag from tissues to blood then becomes a rate-determining step for elimination. Were the same sequence of events true for methohexitone, there would be a much slower decrease in the plasma concentrations of the drag which might be expected to show three phases (that is, to fit a three-compartment kinetic model). The concentrations in the present study 5 or 6 h after infusion were slightly higher than those corresponding to the fitted line of the £-phase. Therefore the fitting procedure was repeated on the assumption of a three-exponential equation underlying the plasma concentrations during and after infusion. A possible fit of the data to a three-compartment system was obtained in only two subjects, but there was a large variation in the fitted coefficients and rate constants. For the other two volunteers a three-compartment system could not be applied to the data. In support of the two-compartment hypothesis is the observation by Brand and others (1963) that methohexitone and hexobarbitone were less extensively localized in human fat than thiopentone. For hexobarbitone Breimer and colleagues (1975) have described the plasma concentration time course in humans, following i.v. infusion, by two-compart54
ment kinetics. If adipose tissue plays only a minor role in the elimination of methohexitone (and hexobarbitone) from human plasma, there is no reason to propose a three-compartment system for the elimination of these drugs. It may be derived from the high clearance constant for methohexitone (table II), that metabolism occurs so rapidly that substantial drug uptake by the poorly perfused fat tissue does not occur. Thus this is an important factor only at very high doses, and the plasma concentrations measured by Brand and others (1963) after i.v. infusion of methohexitone 1.2-1.8 g to four volunteers indicate that there may be a slower phase corresponding to a half-life of 3-5 h. However, they did not study plasma concentrations for a period sufficient to allow definite conclusions; moreover, the specificity of their u.v. assay method for unchanged drug is questionable. There remains the theoretical possibility of a more complex kinetic behaviour of methohexitone than that derived from the present experiments; it is used as a racemic mixture and, as in the case of hexobarbitone, the two enantiomers may differ in elimination rate (Breimer and van Rossum, 1973, 1974b). Sunshine and others (1966) found only small amounts of methohexitone in the urine and bile of man; less than 1% of the administered dose was excreted as unchanged methohexitone. Rapid metabelism seems to be the major reason for the high clearance value and the short half-life of the drug. The apparent volume of distribution is in the same order of magnitude as was found for hexobarbitone (Breimer et al., 1975). In support of the idea that methohexitone is metabolized rapidly is the fact that
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Age (yr) Body-weight (kg) Dose (mg free acid) Dose (kg/mg)f Infusion time (min) Half-life j3-phase (min) Kx/kg (litre) Kd/kg (litre) Clearance (ml min^1) Clearance/kg (ml min- 1 ) k12 (min-1) k21 (min-1)
R. C.
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Breimer, D. D., and de Boer, A. G. (1975). Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium in man after oral administration. Eur. J. Clin. Pharmacol., 9, 169. Honhoff, C , Zilly, W., Richter, E., and van Rossum, J. M. (1975). Pharmacokinetics of hexobarbital in man after intravenous infusion. J. Pharmacokin. Biopharm., 3, 1. van Rossum, J. M. (1973). Pharmacokinetics of ( + )-, ( —)- and ( + )-hexobarbital in man after oral administration. J. Pharm. Pharmacol., 25, 762. (1974a). Rapid and sensitive gas chromatographic determination of hexobarbital in plasma of man using a nitrogen detector. J. Chromatogr., 88, 235. (1974b). Pharmacokinetics of the enantiomers of hexobarbital studied in the same rat and in the same isolated perfused rat liver. Eur.J. Pharmacol., 26, 321. Winten, M. A. C. M. (1976). Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration. Eur. J. Clin. Pharmacol., 9, 443. Clarke, R. S. J., Dundee, J. W., Barron, D. W., and McArdle, L. (1968). Clinical studies of induction agents. XXVI: The relative potencies of thiopentone, methohexitone and propanidid. Br. J. Anaesth., 40, 593. Egbert, L. D., Oech, S. R., and Eckenhoff, J. E. (1959). Comparison of the recovery from methohexital and thiopental anesthesia in man. Surg. Gynecol. Obstet., 109, 427. Elliott, C. J. R., Green, R., Howells, T. H., and Long, H. A. (1962). Recovery from intravenous barbiturate anaesthesia: comparative study of recovery from methohexitone and thiopentone. Lancet, 2, 68. Gibaldi, M., Boyes, R. N., and Feldman, S. (1971). Influence of first-pass effect on availability of drugs on oral administration. J. Pharm. Sci., 60, 1338. ACKNOWLEDGEMENTS Loo, J. C. K., and Riegelman, S. (1970). Assessment of pharmacokinetic constants from postinfusion blood curves The experiments were carried out in the Department of obtained after i.v. infusion. J. Pharm. Sci., 59, 53. Pharmacology, University of Nijmegen, The Netherlands. The author wishes to thank Professor Dr J. M. van Rossum Price, H. L., Kovnat, P. J., Safer, J. N., Cormier, E. H., for valuable and stimulating discussions and Miss C. and Price, M. L. (1960). Uptake of thiopental by body Honhoff for her aid with the curve-fitting procedure. The tissues and its relation to the duration of narcosis. Clin. aid and medical supervision by Professor J. F. Crul and Pharmacol. Ther., 1, 16. Dr J. Duret, Department of Anaesthesiology, University of Riegelman, S., Loo, J. C. K., and Rowland, M. (1968). Nijmegen, are gratefully acknowledged. The excellent Shortcomings in pharmacokinetic analysis by conceiving technical assistance of Mrs C. P. W. G. M. Verweij-van the body to exhibit properties of a single compartment. Wissen in the determination of methohexitone plasma J. Pharm. Sci., 57, 117. concentrations is highly appreciated. van Rossum, J. M. (1971). Significance of pharmacokinetics for drug design and the planning of dosage regimens; in Drug Design (ed. E. J. Ariens), Vol. I, p. 469. New York: REFERENCES Academic Press. Barlow, M. B., and Gottlich, J. (1962). The use of metho- Rowland, M. (1972). Influence of route of administration on hexital to shorten safely the hospitalisation of day cases. drug availability. J. Pharm. Sci., 61, 70. Med. Proc, 8, 458. Sunshine, I., Whitwam, J. G., Fike, W., Finkle, B., and Barry, C. T., Lawson, R., and Davidson, D. G. D. (1967). Lebeau, J. (1966). Distribution and excretion of methoRecovery after methohexitone and thiopentone. Anaeshexitone in man. A study using gas and thin layer thesia, 22, 228. chromatography. Br. J. Anaesth., 38, 23. Brand, L.3 Mark, L. C , Snell, M. McM., Vrindten, P., and Thomas, E. T. (1967). The relative potencies of methoDayton, P. G. (1963). Physiologic disposition of methohexitone and thiopentone. Anaesthesia, 22, 16. hexital in man. Anesthesiology, 24, 331. Whitwam, J. G. (1972). The pharmacology of brietal Breimer, D. D. (1974).*Pharmacokinetics of hypnotic drugs. sodium (methohexitone sodium). Anaesthesiol. Wieder., Ph.D. Thesis, University of Nijmegen, The Netherlands. 57, 1.
the oral administration of methohexitone sodium results in low systemic bioavailability of the drug (Breimer, 1974). Apparently there is a substantial "first-pass" effect, which suggests that the compound is metabolized extensively during first passage through the liver after oral administration (Gibaldi, Boyes and Feldman, 1971; Rowland, 1972). It seems likely that methohexitone will be similar to thiopentone and hexobarbitone in its pattern of distribution immediately after i.v. injection. Rapid recovery of consciousness after a single i.v. dose of each of these drugs is largely a result of a redistribution process from the highly perfused viscera, including the central nervous system, into lean body mass (Price et al., 1960). In addition, it is highly probable that the rapid and complete recovery following methohexitone, as has been reported from many clinical observations (Whitwam, 1972), is a result of the rapid inactivation of the drug by metabolism. This should be considered of great benefit for operations of short duration. It may be mentioned that in the present experiments the volunteers experienced drowsiness and were generally inclined to fall asleep 15 min after the onset of infusion. Throughout the infusion period they could be awakened easily and, after termination of the infusion, recovery appeared to be complete within an hour, as judged by subjective rating.
PHARMACOKINETICS OF METHOHEXITONE PHARMACOCINETIQUE DU METHOHEXITONE APRES ADMINISTRATION INTRAVEINEUSE CHEZ LES HUMAINS RESUME
PHARMAKOKINETISCHE EIGENSCHAFTEN VON METHOHEXITON NACH DESSEN INTRAVENOSER VERABREICHUNG BEIM MENSCHEN ZUSAMMENFASSUNG
Eine sensitive Methode unter Verwendung von Gaschromatographie mit Stickstoff-Selektivfindung wurde entwickelt, um eine genaue Messung von MethohexitonPlasmakonzentrationen durchfuhren zu konnen, in Konzentrationen von weniger als 0,05 ng/ml; dadurch wird es moglich, die pharmakokinetischen Eigenschaften der Droge nach Verabreichung klinischer Dosen beim Men-
schen zu studieren. Methohexitonsodium (3,0 mg/kg) wurde intravenos an gesunde Versuchspersonen verabreicht, wobei wahrend und nach der Verabreichung die Plasmakonzentrationen gemessen wurden. Die Verringerung der Methohexiton-Plasmakonzentration kann durch zweiteilige Kinetik beschrieben werden. Die endgultige Ausscheidungs-Halbwertzeit der Droge ist relativ kurz (70-125 min) als Folge einer hohen metabolischen Ausscheidungsrate (657-999 Plasma/min). Zusammenfassend wurde festgestellt, dass die Aufnahme der Droge durch adipSses Gewebe nicht wesentlich zu ihren pharmakokinetischen Eigenschaften im Menschen beitragt. Zusatzlich zur anfanglichen Neuverteiliung einer narkotischen Dosis von Methohexiton ist die rasche Erholung von Patienten ein Ergebnis des rapiden Metabolismus der Droge. FARMACOCINETICA DE LA METOHEXITONA, CONSECUTIVA A INFUSION ENDOVENOSA EN EL HOMBRE SUMARIO
Un metodo sensitivo, usando cromatografia en fase gaseosa con detection selectiva de nitrogeno, ha sido desarrollado para la medicion exacta de metohexitona en el plasma, en concentraciones menores de 0,05 (J-g/ml, y que hace posible estudiar la farmacocinetica del farmaco tras dosis clinicas en el hombre. Se administro metohexitona sodica (3,0 mg/kg) mediante infusion orden-cero a voluntarios sanos, y se midieron las concentraciones plasmaticas durante y despues de la infusion. El descenso en la concentracion plasmatica de metohexitona puede ser descrito mediante cinetica duocompartamental. La media vida de eliminacion terminal del farmaco es relativamente breve (70 a 125 min), lo que es resultado de un elevado indice de aclaramiento metabolico (657 a 999 ml plasma/min). Se concluyo que la captaci6n del farmaco por el tejido adiposo no contribuye significativamente a su farmacocinetica en el hombre. Ademas de la redistribucion inicial de una dosis anest£sica de metohexitona, la recuperacion rapida de los pacientes es consecuencia del rapido metabolismo del farmaco.
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On a mis au point une technique tres precise basee sur la chromatographie en phase gazeuse avec detection selective de l'azote, pour mesurer les faibles concentrations de methohexitone dans le plasma, pour des concentrations inferieures a 0,05 Kg/ml, technique qui permet d'etudier la pharmacocinetique du medicament apres administration de doses cliniques a l'homme. On a administre en ordre zero des infusions de 3 mg/kg de methohexitone sodium a des volontaires en bonne same puis on en a mesure les concentrations dans le plasma pendant et apres l'infusion. La diminution de la concentration dans le plasma peut etre d£crite comme etant une cinetique a deux compartiments. La demi-vie terminale de l'elimination du medicament est relativement courte (70-125 min), et elle resulte du coefficient d'epuration plasmatique hautement metabolique (657-999 ml de plasma/min). On en a conclu que la fixation du medicament par les tissus adipeux ne contribue pas d'une maniere significative a sa pharmacocinetique chez l'homme. En plus de la redistribution initiale d'une dose anesthesiante de methohexitone, la recuperation rapide des patients resulte du m^tabolisme rapide du medicament.
649
