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Contribution of the Lung to Total Body Clearance of Meperidine in the Dog
Contribution of the Lung to Total Body Clearance of Meperidine in the Dog WILLIAMG. KRAMER*',DAVIDR. GROSS*,AND CYNTHIA MEDLOCK* Received May 2, 1984, from the * Department of Pharmaceutics, University of Houston, Houston, TX 77030 and the *Physiology and Applied Physics Laboratory, Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX, 77843. Accepted for publication January 28, 1985. Abstract 0 The potential role of thle lung in the disposition of meperidine
was examined in six conscious dogs instrumented for measurement of appropriate hemodynamic parameters. Following an intravenous bolus injection of 5 mg/kg, blood samples were collected simultaneously from cannulas placed in the left ventricle and the pulmonary artery, concurrent with the hernodynamic measurements. Pulmonary clearance, calculated from concentration differences between pulmonary arterial and left ventricular blood and pulmonary blood flow, averaged 12.1 f 3.70 mL/min/kg, accounting for 58 & 13%of the total clearance of the drug. These results help resolve differences between previously reported meperidine clearance in the dog and physiological blood flows and imply that the dog may be a poor model for this drug in humans where clearance is primarily hepatic. During a study of the effects of hyperbaric and hyperbaric hyperoxic conditions on the distribution and elimination of meperidine in the dog,' it was observed that the total clearance of the drug exceeded the sum of hepatic and renal blood flows, although its elimination is considered to be almost solely hepatic.* As the lung is capable of drug oxidation as well as drug ~ p t a k ethe , ~ possible role of the lung in meperidine disposition was evaluated.
Experimental Section Materials a n d Methods--Six mixed-breed dogs weighing 26.9 f 5.3 kg were used in this; study. Prior to use, all dogs were vaccinated for common viral diseases, were treated for internal parasites, were negative for Llirofilaria species upon examination of the blood, and were conditioned for a minimum of 3 weeks. The dogs were anesthetized with thiamylal sodium (30 mg/kg). The trachea was iiitubated and the animals were maintained in a surgical plane of anesthesia with appropriate concentrations of halothane. Our surgical procedures for cardiovascular instrumentation have been described, in detail, previ~usly.~ Briefly, using strictly aseptic procedures, silastic cannulas were placed in the descending aorta, the right atrium, the pulmonary artery, and the apex of the left ventricle. An electromagnetic flowmeter transducer (In Vivo Metrics, Inc., Healdsburg, CA) of appropriiate size was placed around the main pulmonary artery. The flowmeter transducers had been previously calibrated using both saline and blood. After sacrificing the dogs, using an overdose of barbiturate, the instrumentation was removed and the flowmeter transducers were recalibrated. A minimum recovery period. of 14-21 d was allowed following instrumentation surgery. During this time, the dogs were handled daily and familiarized with the same laboratory surroundings and conditions that existed during the actual experimental protocol. At the time of the experiments the dogs were minimally restrained on an examination table. Left ventricular and pulmonary artery pressures were measured using #5F NIHstyle catheters with side holes, passed through the pulmonary 0022-3549/85/0500-0569$0 1.00/0 0 1985, American PharmaceuticalAssociation
artery and left ventricular cannulas. These were attached to previously calibrated fluid-filled pressure transducers (model P23dB; Statham Instruments, Inc., Oxnard, CA). The electromagnetic flowmeter transducer was coupled to an electromagnetic flowmeter (Narcomatic Electromagnetic Flowmeter RT500; Narco Bio-Systems, Inc., Houston, TX) and all instrumentation was connected, through appropriate couplers and amplifiers, to a four-channel direct-writing oscillograph (Brush-Gould 2400; Gould Electronics, Cleveland, OH). The use of the electromagnetic flowmeter allowed us to observe transient changes and to identify the time a t which peak changes in cardiac output occurred. Baseline recordings were made of pulsatile and mean (?) pulmonary artery flow (Qpa) and pressure (Ppa),pulsatile left ventricular pressure (PIy),and pulsatile aortic pressure (Pa,,). Preinjection samples of arterial blood, from the left ventricle, and mixed venous blood, from the pulmonary artery, were drawn. A commercial preparation of meperidine hydrochloride (Demerol; Winthrop Labs, New York, NY) was injected at a dose of 5 mg/kg as a bolus into the right atrium. Blood samples were simultaneously collected in heparinized tubes from the pulmonary artery and left ventricular cannulas at 2, 5 , 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, and 180 min postinjection. The cardiovascular parameters were measured continuously throughout the experiment. Blood samples were centrifuged and the plasma removed and frozen until assay. Plasma samples were assayed for meperidine concentration using a GC method;5 all samples were assayed in triplicate and the mean value was used. The pharmacokinetic parameters describing meperidine disposition were calculated from the pulmonary artery concentration-time curve using model-independent or statistical-moment methods? The area under the concentration (C)-time ( t ) curve (AUC) and the first moment (C.t)-time curve (AUMC) were calculated using the Lagrange method7 through the final sampling time with extrapolation to infinity using the apparent elimination rate constant, taken as the negative slope of the terminal log-linear portion of the curve. From AUC, AUMC, and k , the total clearance ( C L ) ,volume of distribution at steady state (Vd,,), mean residence time (MRT), and half-life ( tl,z) were calculated using standard equations.6 Meperidine clearance by the lung, ( C k ) was estimated as follows. For each dog, the pulmonary extraction ratio (E) was calculated according to:
E=
AUCpA - AUCLV AUCPA
(1)
where AUCpAand AUCLv represent the area under the meperidine concentration-time curve, zero to infinity, in the pulmonary artery and left ventricle, respectively; AUCs were calculated as stated above. Pulmonary plasma flow (Qpp) was then calculated from each average pulmonary blood flow, QPB,corrected for hematocrit (HCT), using eq. 2. Lung clearance was Journal of PharmaceuticalSciences / 569 Vol. 74, No. 5, May 1985
Table I-Pharmacokinetic Parameters for Meperidine in the Dog Pulmonary CL, Vd,,, MRT, t,,Z, Weight, Plasma Dog Flow, mL/min L min min kg mLfmin 1 22.0 902 334 20.3 61 88 2 31.2 505 15.1 30 35 1122 3 17.3 913 301 12.7 42 37 4 13.0 257 10.1 39 33 1065 331 14.6 44 35 5 14.5 735 337 19.7 59 71 6 15.4 1076 Mean 969 334 15.4 46 50 18.9 4.0 12 24 6.8 146 85 SD and Pulmonaw Clearance of Meperidine in the Dog Pulmonary Lung CLT’ Extraction Clearance, f~~ Dog mL/min Ratio. % mLlmin 101 0.30 1 334 11.2 153 0.30 2 505 13.6 149 0.49 3 301 16.3 203 0.79 4 257 19.0 0.36 16.4 121 5 331 165 0.49 6 337 15.3 Mean 334 15.3 148 0.46 SD 85 2.7 35 0.18 = fraction cleared by the lung, Le., CLJCLT.
Table Il-Total
Table Ill-Hemodynamic Effects of a Single Bolus Dose (5 mg/kg) of Meperidine Hydrochloride’ Baseline Peak Effect 2.232 0.64 1.45f 0.20’ Q,-X, L/min 16.7 f 3.9 16.7f 3.6 P,-S, mm Hg 9.7 f 2.8 8.8& 2.3 Pp.-_O,mm Hg 11.722.4 11.Of2.0 P,-X, mm Hg 91.O f 3.8’ 99.3& 3.3 P,-S, mm Hg 74.3f 7.3 71.5f 8.8 Pm+, mm Hg 80.5f 5.1 85.3& 4.3 Pm-X,mm Hg 93.0f 4.1’ 101 .O & 3.3 Pi& mm Hg 3.2& 1.3 2.8f 1.2 Plv-D,mm Hg 81.5f 5.6 82.0f 5.5 HR, beats/min 7.81 f 2.22 6.04& 2.95 RWi,mm Hg .min/L 56.6f 9.22 42.7-I- 15.5 R,,.,, mm Hg .min/L Q,, pulmonary arterial flow; P,, pulmonary arterial pressure; Pm, aortic pressure; PI,, left ventricular pressure; HR, heart rate; ,R ,, pulmonary vascular resistance, or:
R,,,
systemic vascular resistance, or:
S, peak systolic; D, end diastolic; X = mean; values reported as mean f SD. Significant at the p < 0.05level.
then:
Results Plasma clearance of meperidine, based upon pulmonary arterial concentrations, averaged 334 & 85 mL/min (mean f SD, Table I). The mean pulmonary extraction ratio was 15.3 k 2.7%, with lung clearance averaging 148 f 35 mL/min and accounting for 46 f 18% of total clearance (Table 11). The steady-state volume of distribution, mean residence time, and half-life averaged 15.4 L, 46 k 12 min, and 50 & 24 min, respectively (Table I). As can be seen in Table 111, there were significant decreases in pulmonary arterial mean flow and peak systolic aortic and left ventricular pressures. The other hemodynamic parameters were not affected by the bolus injection of meperidine hydrochloride. Peak effects were seen within 3-5 min of injection and there was a return to baseline within 10-15 min of injection.
Discussion Ideally, measurement of the pulmonary contribution to the clearance of meperidine should be done under steady-state conditions, where differences in meperidine concentration between the pulmonary artery and left ventricle would be due only to clearance, with no influence from distribution out of or into the blood. However, steady-state studies of meperidine in the dog are difficult to conduct due to the cardiovascular effects of the drug. In studies of conscious, previously instrumented dogs, continuous administration of meperidine has been shown to decrease cardiac output, stroke volume, and heart rate and to increase pulmonary and arterial resistance,s” making it difficult to maintain the animal for a prolonged period. Consequently, our studies were done using a bolus dose, with appropriate analyses of the data, in an attempt to compensate for the problems introduced by the method of administration, i.e., the confounding of the contributions of distribution and clearance to the arterial-venous difference. In addition to the estimation of pulmonary extraction by AUC differences (eq. l ) ,which tends to compensate for distribution effects a t early times by redistribution effects a t later times, E was also calculated at each time according to:
E=
CLL
=E x
Qpp
(3)
570 /Journal of Pharmaceutical Sciences Vol. 74, No. 5,May 1985
(4)
to examine potential changes in E with time. Extraction decreased with time, from 20 to 30% at the early times to -15% at the final sampling times, indicating that initially some of the removal from the blood was due to uptake by the lung. Pulmonary extraction as estimated by eq. 1, however, should provide a more reasonable estimate of the contribution of clearance alone to the pulmonary removal of meperidine. The disposition parameters for meperidine from this study differ from those of our previous study in which the drug was given at a lower dose (1.4 mg/kg) (Table IV). Following a 3.6fold increase in dose, CL decreased by -74% and Vd,, decreased by -70%; thus, there was essentially no change in MRT or tl/’. In the dog, meperidine has been reported to be eliminated almost totally by hepatic metabolism.’ Consequently, the de-
Parameter CL, mL/min/kg Vd,.. Llka ,
of Meperidine Disposition Parameters at
Dose, mg/kg
1287 f 682 334 f 85 15.4f 4.0 54.5f 26.0 55.6f 34.7 49.8f 23.5 f i / z , min 46.9k 21.6 45.8f 12.0 MRT, min a Based upon data reported in ref. 1. Values reported as mean f SD for five dogs. ’Values reported as mean rt SD for six dogs. I
Hemodynamic data were compared as baseline versus peak meperidine effect using the t test for paired data. The p < 0.05 level was chosen for significance based upon our confidence in the repeatability of the measurements.
- CLV
CPA
Table IV-Comparison Low and High Doses
calculated from the extraction ratio and the mean pulmonary plasma flow (eq. 3):
CPA
crease in clearance a t the higher dose may represent a saturation of one of the metabolic pathways. Although no difference in meperidine disposition in humans was seen over this same dose range (5 mg/kg uersus 1.4 rng/kg); similar data have not as yet been reported for the dog nor may the same doseindependent pharmacokinetico apply. The decrease in volume of distribution may be related to changes in binding at the higher dose, or to other factors. Conclusions regarding the absolute contribution of the lung to meperidine pharmacokinetics from the current study cannot, therefore, be extrapolated to those from the lower dose. However, in a qualitative manner, the data from the current study indicate that about one-half of the total clearance of the drug may be accounted for by the pulmonary clearance; in the earlier study, about 40% of the total clearance was unaccounted for by hepatic and renal plasma flow.’ It is apparent, however, that the lung plays a significant role in the disposition of meperidine at the higher dose. It cannot be explicitly determined from the data presented here whether the lung is actually metabolizing meperidine or only taking it up. Although the GC assay used for sample analysis is capable of detecting the metabolite normeperidine; no peaks corresponding to that compound were seen in any sample. Other more polar metabolites are not extracted by this assay. Our hemodynamic results agree, in general, with those published by other investigators who have documented the effects of intravenous bolus injections in intact, awake, previously instrumented dogs. Goldberg et al. injected 2 mg/kg iv and found that cardiac output decreased 30%. They also found a decrease in stroke volume and heart rate with an increase in pulmonary vascular and systemic resistance.” Priano and Vatner used the same dose and found a decrease in aortic pressure, along with a decrease in cardiac output and a significant increase in systemic resistance.“ The systemic resistance in our dogs showed some tendency to increase but it was not significant (Table 111). Priano and Vatner also documented a mild degree of renal vascular dilation. At 6 mg/kg, the latter investigators observed large renal vascular dilation along with increases in heart rate. There was a decrease in mean aortic pressure and an initial increase in cardiac output followed by a decrease. At 6 mg/kg systemic resistance decreased in their study.” Freye found that 2.5 mg/kg, in pentobarbital anesthetized, open thorax preparations, resulted in decreased PI,, Pao, left ventricular dp/dtmax,corcmary sinus blood flow, and myocardial oxygen consumption. There was an increase in heart rate, probably a baroreceptor response.” Although there are
some discrepancies in these results, they can probably be explained by differences in psychic stimulation of the test animals and the normal variability of intact, awake versus anesthetized animal studies. We took special care to acclimate our animals to the test situation and although we did not measure plasma catecholamines, the low resting heart rates and calm demeanor of the animals during the study would indicate a low level of psychic disturbance. There seems to be reproducible evidence of cardiac depression in all of these studies, as evidenced by the decreases in cardiac output and left-side pressures. The results of this study have implications in the use of the dog as a model for the disposition of drugs in humans. Meperidine clearance in humans is reported to be almost solely hepatic13 and its clearance is -70% of liver blood flow. The dog, however, eliminates the drug hepatically: but, as shown in this study, the lung is also significantly involved in its disposition. Thus, this difference in overall disposition would indicate that the dog is a poor model for pharmacokinetic studies of drugs of this type. Of equal importance are the implications with respect to the sampling site for pharmacokinetic studies of drugs cleared by the lung. If the lung is involved in the clearance of a drug, then sampling must be done from the pulmonary artery to appropriately estimate the disposition parameters.
References and Notes 1. Kramer, W. G.; Gross, D. R.; Moreau, P. M.; Fife, W. P. Auiat. Space Enuiron. Med. 1983,54,410-412. 2. Yeh, S. Y.; Krebs, H. A,; Changchit, A. J. Phurrn. Sci. 1981, 70, ~ ~ -,-. 7 - ~ 7 n I-.
3. Roth, R. A.; Wiersma, D. A. Clin. Phurrnacokinet. 1979.4, 355. 4. Gross, D. R.; Kitzman, J. V.; Adams, H. R. Am. J. Vet. Res. 1979, 40,783-791. 5. Koska, A. J., 111; Kramer, W. G.: Romagnoli, A.; Keats, A. S.; Sabawala, P. B. Anesth. Analg. (Cleveland) 1981,60,8-11. 6. Gibaldi, M; Perrier, D. “Pharmacokinetics,”2nd ed.; Dekker: New York, 1982; pp 409-417. 7. Rocci, M. L., Jr.; Jusko, W. J. Comput. Program Biorned. 1983, 16,203-216. 8. Goldberg, S.J.; Linde, L. M.; Wolfe, R. R.; Griswold, W.; Momma, K. Am. Heart J. 1969, 77, 214-221. 9. Priano, L. L.; Vatner, S. F. Anesth. Analg. (Cleueland) 1981,60, 649-654. 10. Goldberg, S.J.; Linde, L. M.; Wolfe, R. R.; Griswold, W.; Momma, K. Am. Heart J . 1969,77,214-221. 11. Priano, L. L.; Vatner, S.F. Anesth. Analg. (Cleueland) 1981,60, 649-654. 12. Freye, E.Anesth. Analg. (Cleueland) 1974,53,40-47. 13. Mather, L. E.; Meffin, P. J. Clin. Pharrnacokinet. 1978, 3, 352368.
Journal of Pharmaceutical Sciences / 571 Vol. 74, No. 5, May 1985
was examined in six conscious dogs instrumented for measurement of appropriate hemodynamic parameters. Following an intravenous bolus injection of 5 mg/kg, blood samples were collected simultaneously from cannulas placed in the left ventricle and the pulmonary artery, concurrent with the hernodynamic measurements. Pulmonary clearance, calculated from concentration differences between pulmonary arterial and left ventricular blood and pulmonary blood flow, averaged 12.1 f 3.70 mL/min/kg, accounting for 58 & 13%of the total clearance of the drug. These results help resolve differences between previously reported meperidine clearance in the dog and physiological blood flows and imply that the dog may be a poor model for this drug in humans where clearance is primarily hepatic. During a study of the effects of hyperbaric and hyperbaric hyperoxic conditions on the distribution and elimination of meperidine in the dog,' it was observed that the total clearance of the drug exceeded the sum of hepatic and renal blood flows, although its elimination is considered to be almost solely hepatic.* As the lung is capable of drug oxidation as well as drug ~ p t a k ethe , ~ possible role of the lung in meperidine disposition was evaluated.
Experimental Section Materials a n d Methods--Six mixed-breed dogs weighing 26.9 f 5.3 kg were used in this; study. Prior to use, all dogs were vaccinated for common viral diseases, were treated for internal parasites, were negative for Llirofilaria species upon examination of the blood, and were conditioned for a minimum of 3 weeks. The dogs were anesthetized with thiamylal sodium (30 mg/kg). The trachea was iiitubated and the animals were maintained in a surgical plane of anesthesia with appropriate concentrations of halothane. Our surgical procedures for cardiovascular instrumentation have been described, in detail, previ~usly.~ Briefly, using strictly aseptic procedures, silastic cannulas were placed in the descending aorta, the right atrium, the pulmonary artery, and the apex of the left ventricle. An electromagnetic flowmeter transducer (In Vivo Metrics, Inc., Healdsburg, CA) of appropriiate size was placed around the main pulmonary artery. The flowmeter transducers had been previously calibrated using both saline and blood. After sacrificing the dogs, using an overdose of barbiturate, the instrumentation was removed and the flowmeter transducers were recalibrated. A minimum recovery period. of 14-21 d was allowed following instrumentation surgery. During this time, the dogs were handled daily and familiarized with the same laboratory surroundings and conditions that existed during the actual experimental protocol. At the time of the experiments the dogs were minimally restrained on an examination table. Left ventricular and pulmonary artery pressures were measured using #5F NIHstyle catheters with side holes, passed through the pulmonary 0022-3549/85/0500-0569$0 1.00/0 0 1985, American PharmaceuticalAssociation
artery and left ventricular cannulas. These were attached to previously calibrated fluid-filled pressure transducers (model P23dB; Statham Instruments, Inc., Oxnard, CA). The electromagnetic flowmeter transducer was coupled to an electromagnetic flowmeter (Narcomatic Electromagnetic Flowmeter RT500; Narco Bio-Systems, Inc., Houston, TX) and all instrumentation was connected, through appropriate couplers and amplifiers, to a four-channel direct-writing oscillograph (Brush-Gould 2400; Gould Electronics, Cleveland, OH). The use of the electromagnetic flowmeter allowed us to observe transient changes and to identify the time a t which peak changes in cardiac output occurred. Baseline recordings were made of pulsatile and mean (?) pulmonary artery flow (Qpa) and pressure (Ppa),pulsatile left ventricular pressure (PIy),and pulsatile aortic pressure (Pa,,). Preinjection samples of arterial blood, from the left ventricle, and mixed venous blood, from the pulmonary artery, were drawn. A commercial preparation of meperidine hydrochloride (Demerol; Winthrop Labs, New York, NY) was injected at a dose of 5 mg/kg as a bolus into the right atrium. Blood samples were simultaneously collected in heparinized tubes from the pulmonary artery and left ventricular cannulas at 2, 5 , 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, and 180 min postinjection. The cardiovascular parameters were measured continuously throughout the experiment. Blood samples were centrifuged and the plasma removed and frozen until assay. Plasma samples were assayed for meperidine concentration using a GC method;5 all samples were assayed in triplicate and the mean value was used. The pharmacokinetic parameters describing meperidine disposition were calculated from the pulmonary artery concentration-time curve using model-independent or statistical-moment methods? The area under the concentration (C)-time ( t ) curve (AUC) and the first moment (C.t)-time curve (AUMC) were calculated using the Lagrange method7 through the final sampling time with extrapolation to infinity using the apparent elimination rate constant, taken as the negative slope of the terminal log-linear portion of the curve. From AUC, AUMC, and k , the total clearance ( C L ) ,volume of distribution at steady state (Vd,,), mean residence time (MRT), and half-life ( tl,z) were calculated using standard equations.6 Meperidine clearance by the lung, ( C k ) was estimated as follows. For each dog, the pulmonary extraction ratio (E) was calculated according to:
E=
AUCpA - AUCLV AUCPA
(1)
where AUCpAand AUCLv represent the area under the meperidine concentration-time curve, zero to infinity, in the pulmonary artery and left ventricle, respectively; AUCs were calculated as stated above. Pulmonary plasma flow (Qpp) was then calculated from each average pulmonary blood flow, QPB,corrected for hematocrit (HCT), using eq. 2. Lung clearance was Journal of PharmaceuticalSciences / 569 Vol. 74, No. 5, May 1985
Table I-Pharmacokinetic Parameters for Meperidine in the Dog Pulmonary CL, Vd,,, MRT, t,,Z, Weight, Plasma Dog Flow, mL/min L min min kg mLfmin 1 22.0 902 334 20.3 61 88 2 31.2 505 15.1 30 35 1122 3 17.3 913 301 12.7 42 37 4 13.0 257 10.1 39 33 1065 331 14.6 44 35 5 14.5 735 337 19.7 59 71 6 15.4 1076 Mean 969 334 15.4 46 50 18.9 4.0 12 24 6.8 146 85 SD and Pulmonaw Clearance of Meperidine in the Dog Pulmonary Lung CLT’ Extraction Clearance, f~~ Dog mL/min Ratio. % mLlmin 101 0.30 1 334 11.2 153 0.30 2 505 13.6 149 0.49 3 301 16.3 203 0.79 4 257 19.0 0.36 16.4 121 5 331 165 0.49 6 337 15.3 Mean 334 15.3 148 0.46 SD 85 2.7 35 0.18 = fraction cleared by the lung, Le., CLJCLT.
Table Il-Total
Table Ill-Hemodynamic Effects of a Single Bolus Dose (5 mg/kg) of Meperidine Hydrochloride’ Baseline Peak Effect 2.232 0.64 1.45f 0.20’ Q,-X, L/min 16.7 f 3.9 16.7f 3.6 P,-S, mm Hg 9.7 f 2.8 8.8& 2.3 Pp.-_O,mm Hg 11.722.4 11.Of2.0 P,-X, mm Hg 91.O f 3.8’ 99.3& 3.3 P,-S, mm Hg 74.3f 7.3 71.5f 8.8 Pm+, mm Hg 80.5f 5.1 85.3& 4.3 Pm-X,mm Hg 93.0f 4.1’ 101 .O & 3.3 Pi& mm Hg 3.2& 1.3 2.8f 1.2 Plv-D,mm Hg 81.5f 5.6 82.0f 5.5 HR, beats/min 7.81 f 2.22 6.04& 2.95 RWi,mm Hg .min/L 56.6f 9.22 42.7-I- 15.5 R,,.,, mm Hg .min/L Q,, pulmonary arterial flow; P,, pulmonary arterial pressure; Pm, aortic pressure; PI,, left ventricular pressure; HR, heart rate; ,R ,, pulmonary vascular resistance, or:
R,,,
systemic vascular resistance, or:
S, peak systolic; D, end diastolic; X = mean; values reported as mean f SD. Significant at the p < 0.05level.
then:
Results Plasma clearance of meperidine, based upon pulmonary arterial concentrations, averaged 334 & 85 mL/min (mean f SD, Table I). The mean pulmonary extraction ratio was 15.3 k 2.7%, with lung clearance averaging 148 f 35 mL/min and accounting for 46 f 18% of total clearance (Table 11). The steady-state volume of distribution, mean residence time, and half-life averaged 15.4 L, 46 k 12 min, and 50 & 24 min, respectively (Table I). As can be seen in Table 111, there were significant decreases in pulmonary arterial mean flow and peak systolic aortic and left ventricular pressures. The other hemodynamic parameters were not affected by the bolus injection of meperidine hydrochloride. Peak effects were seen within 3-5 min of injection and there was a return to baseline within 10-15 min of injection.
Discussion Ideally, measurement of the pulmonary contribution to the clearance of meperidine should be done under steady-state conditions, where differences in meperidine concentration between the pulmonary artery and left ventricle would be due only to clearance, with no influence from distribution out of or into the blood. However, steady-state studies of meperidine in the dog are difficult to conduct due to the cardiovascular effects of the drug. In studies of conscious, previously instrumented dogs, continuous administration of meperidine has been shown to decrease cardiac output, stroke volume, and heart rate and to increase pulmonary and arterial resistance,s” making it difficult to maintain the animal for a prolonged period. Consequently, our studies were done using a bolus dose, with appropriate analyses of the data, in an attempt to compensate for the problems introduced by the method of administration, i.e., the confounding of the contributions of distribution and clearance to the arterial-venous difference. In addition to the estimation of pulmonary extraction by AUC differences (eq. l ) ,which tends to compensate for distribution effects a t early times by redistribution effects a t later times, E was also calculated at each time according to:
E=
CLL
=E x
Qpp
(3)
570 /Journal of Pharmaceutical Sciences Vol. 74, No. 5,May 1985
(4)
to examine potential changes in E with time. Extraction decreased with time, from 20 to 30% at the early times to -15% at the final sampling times, indicating that initially some of the removal from the blood was due to uptake by the lung. Pulmonary extraction as estimated by eq. 1, however, should provide a more reasonable estimate of the contribution of clearance alone to the pulmonary removal of meperidine. The disposition parameters for meperidine from this study differ from those of our previous study in which the drug was given at a lower dose (1.4 mg/kg) (Table IV). Following a 3.6fold increase in dose, CL decreased by -74% and Vd,, decreased by -70%; thus, there was essentially no change in MRT or tl/’. In the dog, meperidine has been reported to be eliminated almost totally by hepatic metabolism.’ Consequently, the de-
Parameter CL, mL/min/kg Vd,.. Llka ,
of Meperidine Disposition Parameters at
Dose, mg/kg
1287 f 682 334 f 85 15.4f 4.0 54.5f 26.0 55.6f 34.7 49.8f 23.5 f i / z , min 46.9k 21.6 45.8f 12.0 MRT, min a Based upon data reported in ref. 1. Values reported as mean f SD for five dogs. ’Values reported as mean rt SD for six dogs. I
Hemodynamic data were compared as baseline versus peak meperidine effect using the t test for paired data. The p < 0.05 level was chosen for significance based upon our confidence in the repeatability of the measurements.
- CLV
CPA
Table IV-Comparison Low and High Doses
calculated from the extraction ratio and the mean pulmonary plasma flow (eq. 3):
CPA
crease in clearance a t the higher dose may represent a saturation of one of the metabolic pathways. Although no difference in meperidine disposition in humans was seen over this same dose range (5 mg/kg uersus 1.4 rng/kg); similar data have not as yet been reported for the dog nor may the same doseindependent pharmacokinetico apply. The decrease in volume of distribution may be related to changes in binding at the higher dose, or to other factors. Conclusions regarding the absolute contribution of the lung to meperidine pharmacokinetics from the current study cannot, therefore, be extrapolated to those from the lower dose. However, in a qualitative manner, the data from the current study indicate that about one-half of the total clearance of the drug may be accounted for by the pulmonary clearance; in the earlier study, about 40% of the total clearance was unaccounted for by hepatic and renal plasma flow.’ It is apparent, however, that the lung plays a significant role in the disposition of meperidine at the higher dose. It cannot be explicitly determined from the data presented here whether the lung is actually metabolizing meperidine or only taking it up. Although the GC assay used for sample analysis is capable of detecting the metabolite normeperidine; no peaks corresponding to that compound were seen in any sample. Other more polar metabolites are not extracted by this assay. Our hemodynamic results agree, in general, with those published by other investigators who have documented the effects of intravenous bolus injections in intact, awake, previously instrumented dogs. Goldberg et al. injected 2 mg/kg iv and found that cardiac output decreased 30%. They also found a decrease in stroke volume and heart rate with an increase in pulmonary vascular and systemic resistance.” Priano and Vatner used the same dose and found a decrease in aortic pressure, along with a decrease in cardiac output and a significant increase in systemic resistance.“ The systemic resistance in our dogs showed some tendency to increase but it was not significant (Table 111). Priano and Vatner also documented a mild degree of renal vascular dilation. At 6 mg/kg, the latter investigators observed large renal vascular dilation along with increases in heart rate. There was a decrease in mean aortic pressure and an initial increase in cardiac output followed by a decrease. At 6 mg/kg systemic resistance decreased in their study.” Freye found that 2.5 mg/kg, in pentobarbital anesthetized, open thorax preparations, resulted in decreased PI,, Pao, left ventricular dp/dtmax,corcmary sinus blood flow, and myocardial oxygen consumption. There was an increase in heart rate, probably a baroreceptor response.” Although there are
some discrepancies in these results, they can probably be explained by differences in psychic stimulation of the test animals and the normal variability of intact, awake versus anesthetized animal studies. We took special care to acclimate our animals to the test situation and although we did not measure plasma catecholamines, the low resting heart rates and calm demeanor of the animals during the study would indicate a low level of psychic disturbance. There seems to be reproducible evidence of cardiac depression in all of these studies, as evidenced by the decreases in cardiac output and left-side pressures. The results of this study have implications in the use of the dog as a model for the disposition of drugs in humans. Meperidine clearance in humans is reported to be almost solely hepatic13 and its clearance is -70% of liver blood flow. The dog, however, eliminates the drug hepatically: but, as shown in this study, the lung is also significantly involved in its disposition. Thus, this difference in overall disposition would indicate that the dog is a poor model for pharmacokinetic studies of drugs of this type. Of equal importance are the implications with respect to the sampling site for pharmacokinetic studies of drugs cleared by the lung. If the lung is involved in the clearance of a drug, then sampling must be done from the pulmonary artery to appropriately estimate the disposition parameters.
References and Notes 1. Kramer, W. G.; Gross, D. R.; Moreau, P. M.; Fife, W. P. Auiat. Space Enuiron. Med. 1983,54,410-412. 2. Yeh, S. Y.; Krebs, H. A,; Changchit, A. J. Phurrn. Sci. 1981, 70, ~ ~ -,-. 7 - ~ 7 n I-.
3. Roth, R. A.; Wiersma, D. A. Clin. Phurrnacokinet. 1979.4, 355. 4. Gross, D. R.; Kitzman, J. V.; Adams, H. R. Am. J. Vet. Res. 1979, 40,783-791. 5. Koska, A. J., 111; Kramer, W. G.: Romagnoli, A.; Keats, A. S.; Sabawala, P. B. Anesth. Analg. (Cleveland) 1981,60,8-11. 6. Gibaldi, M; Perrier, D. “Pharmacokinetics,”2nd ed.; Dekker: New York, 1982; pp 409-417. 7. Rocci, M. L., Jr.; Jusko, W. J. Comput. Program Biorned. 1983, 16,203-216. 8. Goldberg, S.J.; Linde, L. M.; Wolfe, R. R.; Griswold, W.; Momma, K. Am. Heart J. 1969, 77, 214-221. 9. Priano, L. L.; Vatner, S. F. Anesth. Analg. (Cleueland) 1981,60, 649-654. 10. Goldberg, S.J.; Linde, L. M.; Wolfe, R. R.; Griswold, W.; Momma, K. Am. Heart J . 1969,77,214-221. 11. Priano, L. L.; Vatner, S.F. Anesth. Analg. (Cleueland) 1981,60, 649-654. 12. Freye, E.Anesth. Analg. (Cleueland) 1974,53,40-47. 13. Mather, L. E.; Meffin, P. J. Clin. Pharrnacokinet. 1978, 3, 352368.
Journal of Pharmaceutical Sciences / 571 Vol. 74, No. 5, May 1985