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dices and pethidine disposition were carried out in sheep according to standardized procedures deve- loped to study, concurrently, interactions between.
Br. J. Anaesth. (1986), 58, 888-896

A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRUG DISPOSITION V: THE EFFECTS OF GENERAL AND SUBARACHNOID ANAESTHESIA ON BLOOD FLOW AND PETHIDINE DISPOSITION L. E. MATHER, W. B. RUNCIMAN, A. H. ILSLEY, R. J. CARAPETIS AND R. N. UPTON

Since general and subarachnoid anaesthesia may induce variability in the cardiovascular system (Prys-Roberts, 1980; Greene, 1981), we have studied the influence of such effects on the disposition of selected drugs with potentially flowlimited clearances, using sheep with chronically implanted catheters (Runciman, Ilsley et al., 1984; Runciman, Mather et al., 1984a). In this paper, studies on the disposition of pethidine are presented. Pethidine was chosen because it is used commonly in the peri-operative period, is eliminated principally by the liver (Mather and Meffin, 1978; Edwards et al., 1982), and has minimal cardiovascular effects at the blood concentrations which produce analgesia (Jaffe and Martin, 1980). Although the blood concentration-analgesic response relationship in patients following surgery is steep (Austin, Stapleton and Mather, 1980), the nature of the blood concentration-respiratory response is not known. However, it is known that depression of the ventilatory response to carbon dioxide occurs in healthy volunteers at blood concentrations required to produce analgesia in postoperative patients (Rigg, Ilsley and Vedig, 1981). Therefore, the potential exists for adverse effects to occur in the perioperative period if the blood concentrations of pethidine increase unexpectedly.

L A U R E N C E E. M A T H E R , P H . D . , F.F.A.R.A.C.S.; W I L L I A M B.

RUN-

CIMAN, F.F.A.R.A.C.S., PH.D.; ANTHONY H . ILSLEY, PH.D.; RONDA J. CARAPBTIS, DIP. LAB. MED.; RlCHARD N . UPTON,

B.SC.; Department of Anaesthesia and Intensive Care, Flinders Medical Centre, The Flinders University of South Australia, Adelaide, S.A. 5042, Australia.

SUMMARY Blood flow through and pethidine extraction ratios across lungs, liver, kidneys and the gastrointestinal tract were measured in awake unrestrained sheep (controls) and with the animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid block with amethocaine. In the control studies, pethidine infused to several times the blood concentrations required for postoperative analgesia in man produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flow); pethidine hepatic extraction ratios were consistently greater than 0.97; renal extraction ratios ranged from negligible to 0.30; and there was negligible extraction across the lungs and the gastrointestinal tract. Under general anaesthesia there were significant reductions in mean cardiac output (46%), mean hepatic blood flow (46%), mean renal blood flow (55%), mean arterial pressure (30%) and mean iodohippurate clearance (17%); but mean arterial blood concentrations of pethidine were doubled, mean hepatic clearance of pethidine was reduced to 60% of control and renal clearance was virtually abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in pethidine or iodohippurate extraction ratios or clearances. Summed measured regional clearances accounted for only one- to two-thirds of the total body clearance of pethidine; the rest was by extravisceral clearance or high affinity tissue binding.

GA OR SA AND PETHIDINE DISPOSITION MATERIALS AND METHODS

Design of study

The studies into the effects of general and subarachnoid anaesthesia on haemodynamic indices and pethidine disposition were carried out in sheep according to standardized procedures developed to study, concurrently, interactions between bloodflowand drug disposition. The rationale for the choice of species, the preparation of the animals for study, and the demonstration of the maintenance of normal physiological function for the duration of each study have been presented previously (Runciman, Ilsley et al., 1984; Runciman, Mather et al., 1984a,b). A brief description of those aspects pertaining to the disposition of pethidine is presented here. Sheep were acclimatized to metabolic crates and then, under general anaesthesia, multiple intravascular catheters, including a left renal vein, a right hepatic vein and a pulmonary artery catheter were placed via the right jugular vein. A portal vein catheter was placed at laparotomy, and aortic catheters were placed via the right carotid artery. On recovery, these catheters were attached to a flushing system, and 2 weeks were allowed for the sheep to recover from the procedure. Cardiac output was measured by thermodilution, renal blood flow by the Fick method using sodium m I-iodohippurate (IOH) and hepatic blood flow using the indicator dilution principle with IOH infused to a mesenteric vein (Runciman, Ilsley et al., 1984). By sampling simultaneously from the catheters, blood flow through, and pethidine and IOH extraction ratios across, the lungs, kidney, liver and gastrointestinal tract could be measured repeatedly. Three studies in sheep under general anaesthesia with 1.5% halothane (studies designated GA 1-GA3) were each compared with control-drug studies in the same animals awake (C1-C3). Three studies in sheep under high thoracic subarachnoid anaesthesia (to approximately T4) (SAi-SAiii) were each compared with control-drug studies in the same animals (Ci-Ciii). Study pairs were separated by at least 2 days. In each control-drug study, control measurements of cardiac output, renal and hepatic bloodflows,arterial pressure and heart rate were obtained every 10 min for 1 h (seven sets). Pethidine hydrochloride was then infused to the right atrium using a two-stage infusion technique designed to achieve steadystate conditions rapidly: a loading infusion of

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between 10.6 and 11.9 mg min"1 for 15 min was followed immediately by a maintenance infusion of between 4.6 and 4.8 mg min"1 for 75 min. Arterial blood samples were taken every 5 min for 30 min after the start of the pethidine loading infusion and for 30 min after cessation of the maintenance infusion. Haemodynamic measurements and blood samples from all appropriate sites were obtained every 10 min during the pethidine maintenance infusion. The last 60-min period of the pethidine maintenance infusion was regarded as the basis for determining pethidine disposition data and the comparison of haemodynamic data with those obtained in the control period before infusion of pethidine. In each general anaesthesia study, the control period was shortened to four sets of measurements made 10 min apart. Anaesthesia was induced with thiopentone 20 mg kg"1 i.v., a cuffed tracheal tube was inserted, and anaesthesia was maintained with halothane in 40% oxygen (balance nitrogen). A constant volume ventilator provided ventilation of the lungs. The vaporizer and ventilator were adjusted to maintain expired halothane concentrations at 1.5% and expired carbon dioxide concentrations at 5%. After the induction of anaesthesia, the sheep was placed in its "normal" lying position with its legs tucked comfortably beneath it. The sternum and forelegs were supported on a foam rubber bolster so that the abdomen was not subject to compression. After 60 min, pethidine was infused and measurements obtained using a regimen identical to that in the control-drug study. Saline (0.9%, up to a total of 200 ml) was infused i.v. as required; mean arterial pressure was maintained within 30 % of control values. In each subarachnoid anaesthesia study, four sets of control measurements were made, as in the general anaesthesia studies. After skin preparation, a 20-gauge spinal needle was inserted to the subarachnoid space in the lumbar region and 1 % amethocaine 5 ml was injected over 5 s with barbotage. Saline (0.9%, up to a total of 200 ml) was infused i.v. at this stage; mean arterial pressure was maintained within 18% of control values. The block was allowed to stabilize and the posture of the sheep was adjusted as in the general anaesthesia studies. The segmental level of blockade was monitored by observing reflex flicking of the skin in response to prodding with a finger (Lebeaux, 1975). After 60 min, pethidine was infused and measurements were made

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according to the regimen used in the control-drug and general anaesthesia studies. Blockade did not start to regress until 160 min had elapsed, but had always started to regress by 180 min. The measurements of haemodynamic function obtained during the last 60 min of the pethidine maintenance infusion in each general anaesthesia and subarachnoid anaesthesia study were each expressed as a percentage of the mean value of the corresponding variable on that day in the same animal during the control period preceding the drug infusion, and were compared using Student's t test. As the effects of general and subarachnoid anaesthesia on regional blood flow and oxygen tension have been discussed in detail in a separate communication (Runciman, Mather et al., 1984b), only those haemodynamic changes which directly affect the measurement or interpretation of the disposition of pethidine are reported in this paper.

BRITISH JOURNAL OF ANAESTHESIA hypothetical clearance in the absence of any limitation imposed by hepatic perfusion, was calculated from the ratio of the mean hepatic clearance of pethidine to transmitted fraction (1—hepatic extraction ratio) (Wilkinson and Shand, 1975; Branch, 1982). This assumed that the hepatic clearance of pethidine was adequately represented by the "well stirred" model—a finding that has been justified for rat liver in vitro (Ahmad, Bennett and Rowland, 1983). The disposition characteristics of pethidine during each general and subarachnoid anaesthesia study were each expressed as percentages of the mean value of the corresponding variable during the control-drug study in the same animal, and were compared using Student's t test for paired data.

RESULTS

Control-drug studies Pethidine analysis and disposition

Pethidine concentrations in whole blood were determined by gas—liquid chromatography with nitrogen selective detection after solvent extraction (Mather and Tucker, 1974), with the exception that lignocaine was used as internal standard. Norpethidine concentrations were determined semi-quantitatively by retrospective calculation from gas chromatograms (Austin, Stapleton and Mather, 1981). Pethidine was infused as the hydrochloride salt, but amounts and concentrations were expressed as the base. Pethidine clearances by lungs, kidney, liver and gastrointestinal tract were determined from the products of blood flows through and extraction ratios across the relevant organs during the last 60 min of the pethidine maintenance infusion. Mean total body clearance was determined from the ratio of the maintenance infusion rate to the mean arterial blood concentration during this period. These calculations are derived from the application of the Fick Principle. Thus, strictly, they apply to steady-state conditions which, in fact, were not achieved in every study. Non-steadystate would tend to underestimate the mean total body clearance and overestimate the regional clearances. However, the consequence of such errors was judged to be insignificant from comparison with results derived from integrated drug concentration curves. To assist in the interpretation of the effects of anaesthesia, the mean hepatic intrinsic clearance, that is the

During the last 60 min of the pethidine maintenance infusion, the mean values for the haemodynamic and IOH kinetic indices were within 8 % of their corresponding control values, with the exception of the cardiac output (table I). Also during this period, there was a tendency for cardiac output to increase and for the renal fraction of cardiac output to decrease. However, these changes to, respectively, 119 (SD 18) and 83 (SD 9)% of control values, were not statistically significant. There was no consistent net pulmonary or prehepatic extraction of pethidine during the last 60 min of the pethidine maintenance infusion. In all control-drug studies, the mean steady-state hepatic extraction ratios of pethidine were greater than 0.97 and the mean renal extraction ratios ranged from a negligible value to 0.3 (mean 0.23, SD 0.10) (tables II and III). The total clearance of pethidine in the six control-drug studies calculated by summing the mean renal, hepatosplanchnic and pulmonary clearances accounted for a mean of only 54 (SD 21)% of the mean total body clearance calculated from the pethidine arterial blood concentrations (tables II and III). The difference, which accounts for up to twothirds of the total pethidine clearance in the individual studies (tables III and IV), would appear to be the result of either "extra-visceral" clearance or substantial pethidine blood-tissue concentration disequilibrium. Preliminary studies had confirmed that pethidine was not metabolized

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TABLE I. Effects ofpethidine on bloodflowin the control-drug studies. Values for cardiac output (CO), hepatic bloodflow(HBF), and renal bloodflow(RBF), iodohippurate renal extraction ratio (IOH ER) and clearance (IOH Cl) before the pethidine infusion in the control-drug studies ( Q may be compared with values obtained during the last 60 min of the pethidine maintenance infusion During pethidine infusion (6 sets of determinations, 10 min apart over 60 min)

Before pethidine infusion (7 sets of determinations, 10 min apart over 60 min) CO (litre min"')

HBF (litre min"')

IOHC/ RBF (litre (litre min"') IOHER min"1)

CO (litre min"')

HBF (litre min"1)

IOHC/ RBF (litre (litre min~') IOHER min"1)

4.0 (0.2)

0.96 (0.18)

0.46 (0.02)

0.67 (0.02)

0.30 (0.01)

4.0 (0.2)

0.92 (0.04)

0.52 (0.03)

0.61 (0.02)

0.32 (0.01)

3.2 (0.4)

0.89 (0.14)

0.53 (0.03)

0.50 (0.02)

0.26 (0.01)

3.8 (0.2)

1.14 (0.23)

0.51 (0.03)

0.51 (0.02)

0.26 (0.01)

3.4 (0.3)

1.00 (0.16)

0.75 (0.08)

0.68 (0.05)

0.61 (0.10)

4.9 (0.1)

1.12 (0.11)

0.75 (0.03)

0.67 (0.01)

0.50 (0.01)

Ci Mean SD

3.7 (0.4)

1.04 (0.06)

0.82 (0.08)

0.69 (0.05)

0.56 (0.02)

5.0 (0.4)

1.36 (0.16)

0.76 (0.05)

0.69 (0.03)

0.52 (0.02)

Cii Mean SD

4.1 (0.4)

1.83 (0.42)

0.93 (0.04)

0.73 (0.02)

0.68 (0.02)

4.6 (0.3)

1.98 (0.56)

0.87 (0.04)

0.70 (0.02)

0.60 (0.02)

Ciii Mean SD

3.9 (0.7)

1.83 (0.10)

0.94 (0.09)

0.70 (0.03)

0.70 (0.03)

4.1 (0.2)

1.9 (0.39)

0.83 (0.03)

0.72 (0.01)

0.72 (0.01)

Study Cl Mean SD C2 Mean SD C3 Mean SD

TABLE II. Effects of general anaesthesia on pethidine disposition. Values for pethidine steady state arterial blood concentrations (Cb), mean total body clearance (Cl), hepatic extraction ratio (ERh) and clearance (CIA), renal extraction ratio (ERr) and clearance (Clr) for the last 60 min of the pethidine maintenance infusion in the control-drug (C) studies may be compared with those in the same animal during the corresponding period in general anaesthesia (GA) studies. ~ 0 = Negligible value Control-drug studies (7 sets of determinations, 10 min apart)

Study

Cb (mg litre"')

Cl Mean 3.1 SD (0.45) C2 Mean 2.1 SD (0.40) C3 Mean 1.2 SD (0.03)

Cl (litre min"')

General anaesthesia studies (6 sets of determinations, 10 min apart)

ERh

C/h (litre min"')

ERr

Ck (litre min-')

1.4

0.97 (0.03)

0.90 (0.05)

0.16 (0.07)

0.08 (0.03)

2.2

0.98 (0.01)

1.16 (0.27)

0.30 (0.15)

0.15 (0.08)

3.9

0.98 (0)

1.16 (0.11)

~0

~0

Study

Cb (mg litre"')

GA1 7.3 Mean (0.68) SD GA2 7.3 Mean (1.2) SD GA3 Mean 2.0 (0.34) SD

Cl (litre min"')

cm

Ck (litre min-')

ERh

(litre min"1)

0.65

0.93 (0.06)

0.40 (0.05)

~0

~0

0.59

0.94 (0.05)

0.51 (0.17)

~0

~0

2.3

0.88 (0.03)

1.06 (0.15)

~0

~0

ERr

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TABLE III. Effects ofsubarachnoid anaesthesia on pethidine disposition. Values for pethidine arterial blood concentration (Cb), mean total body clearance (Cl), hepatic extraction ratio (ERh) and clearance (CIA), renal extraction ratio (ERr) and clearance (Clr) for the last 60 min of the pethidine maintenance infusion in the control-drug ( O studies may be compared with those in the same animal during the corresponding period in subarachnoid anaesthesia (SA) studies Subarachnoid anaesthesia studies (6 sets of determinations, 10 min apart)

Control-drug studies (7 sets of determinations, 10 min apart)

Study

Cb (ing litre"1)

Cl (litre min-')

1.1 (0.27)

ERh

Clh (litre min"')

ERr

C/r (litre min"1)

4.3

0.99 (0.004)

1.35 (0.16)

0.32 (0.09)

0.24 (0.07)

1.3 (0.69)

3.7

0.99 (0.01)

1.96 (0.56)

0.24 (0.19)

0.20 (0.17)

1.0 (0.36)

4.5

0.99 (0)

1.88 (0.39)

0.31 (0.06)

0.26 (0.03)

Ci Mean SD Cii Mean SD Ciii Mean SD

Study

Cb (mg litre-')

Cl (litre min"')

SAi Mean 1.1 (SD) (0.16) SAii Mean 0.63 (SD) (0.12) SAiii Mean 1.3 (SD) (0.15)

ERh

Clh (litre min" 1 )

ERr

C/r (litre min"1)

3.3

1.33 0.99 (0.005) (0.24)

0.12 (0.18)

0.09 (0.14)

7.9

1.32 0.98 (0.005) (0.23)

0.45 (0.06)

0.35 (0.05)

3.6

0.99 1.73 (0.004) (0.13)

0.22 (0.14)

0.17 (0.11)

TABLE IV. Effects of general anaesthesia (GA) and pethidine infusion on blood flow. Values for cardiac output (CO), hepatic blood flow (HBF) and renal blood flow (RBF) in the control period before the general anaesthesia may be compared with values obtained during the last 60 min of the pethidine maintenance infusion during general anaesthesia Before GA and pethidine infusion During GA and pethidine infusion (4 sets of determinations, 10 min apart over 30 min) (6 sets of determinations, 10 min apart over 60 min) Study GA1 Mean SD GA2 Mean SD GA3 Mean SD

HBF

CO

HBF

RBF

(litre min-')

(litre min"')

(litre min"')

CO (litre min")

(litre min"1)

(litre min"1)

RBF

4.1 (0.2)

1.15 (0.18)

0.54 (0.06)

1.5 (0.30)

0.44 (0.06)

0.22 (0.02)

3.5 (0.1)

1.01 (0.09)

0.62 (0.05)

1.7 (0.5)

0.53 (0.16)

0.29 (0.03)

3.9 (0.3)

1.73 (0.07)

0.92 (0.12)

3.0 (0.2)

1.21 (0.2)

0.45 (0.04)

or otherwise degraded in blood in vitro under the 100 to 70 mm Hg and mean heart rate increased conditions imposed by these studies. from 128 to 132 beat min-1. The effects of general anaesthesia on pethidine General anaesthesia studies blood concentrations and clearances are shown in Under general anaesthesia, there were significant figure 1 and table II, and a summary of the decreases in cardiac output, hepatic bloodflowand relevant results is presented in figure 2. It is renal bloodflow(P < 0.05, one tail test) (table IV). evident that the blood concentrations of pethidine These were similar to those reported previously to were doubled, that renal clearance was virtually occur under general anaesthesia (Runciman, abolished, and that hepatic extraction was decreaMather et al., 1984b). However, the renal and sed under general anaesthesia. Mean total body hepatic fractions of cardiac output remained clearance was reduced to 44% of that in the within 10% of their control values. Under general control-drug studies (P < 0.05, one-tail test). The anaesthesia, mean arterial pressure decreased from pethidine hepatic extraction ratio, clearance and

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893

Control

SA

Control 2000

A 200

Time(mln)

200

Time (mln)

FIG. 1. Typical paired pethidine control-drug and anaesthesia studies. The arrows denote the beginning and ending of the pethidine infusion. Note the large arterial-hepatic vein and small arterial-renal vein pethidine concentration differences. Blood concentrations of pethidine in control-drug studies (A and E) may be compared with corresponding general (GA) (B) and subarachnoid (SA) (p) anaesthesia studies. Pethidine clearances in control drug-studies (c and G) may be compared with corresponding general (D) and subarachnoid (H) anaesthesia studies. The apparent negative clearance in D is caused by pethidine redistribution within the organ following the abrupt change from loading to maintenance infusion rate. O — O => Arterial; • • = pulmonary; ' • - - - • = hepatic; A ' • ' • =- renal.

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894 p 100,

Hepatic extraction "ralio

lo

Intrinsic clearance

Clearance

FIG. 2. Effects of anaesthesia on pethidine hepatic kinetics. The mean values and standard deviations of the pethidine hepatic extraction ratio, clearance and hepatic intrinsic clearance during the steady-state period of GA (cross-hatched columns) and SA (stippled columns) studies were each expressed as percentages of the mean value of the corresponding parameter in the control-drug study (black columns) in the same animal. *P < 0.05.

intrinsic clearance under general anaesthesia decreased to mean values of 94, 60 and 16 % of the corresponding values observed during the controldrug studies (P < 0.06, one-tail test) (table III). During general anaesthesia, the mean sum of the directly measured organ clearances of pethidine was 58 % of the corresponding mean of the total body clearances (table II). Hepatic venous blood concentrations of the metabolite, norpethidine, were five- to 10-fold greater than those in the control-drug studies.

control period on that day, with the exception of the cardiac output, which increased to a mean value of 126% of its control value; hepatic and renal fractions of cardiac output were decreased correspondingly (table V). Arterial pethidine concentrations and renal and hepatic extraction ratios remained essentially unaltered under subarachnoid anaesthesia (fig. 1, table V). A summary of the relevant results is presented in figure 2. Pethidine hepatic extraction ratio, clearance and intrinsic clearance were, respectively, means of 100, 86 and 80% of their corresponding values in control-drug studies. Pethidine renal extraction ratio and clearance were, respectively, means of 99 and 92 % of their corresponding values in control-drug studies. None of these changes was significant statistically. The somewhat decreased mean hepatic and mean intrinsic hepatic clearances were attributable to the fact that, in study SAii, the hepaticflowunder subarachnoid anaesthesia was only 68% of its control value, whereas the hepatic flows were 99 and 92% of their respective control values in studies SAi and SAiii; thus mean hepatic flow for all the subarachnoid anaesthesia studies was 86 % of the mean control value. The sum of the hepatic, renal and pulmonary clearances comprised 39 % of the total body clearance during the subarachnoid anaesthesia studies.

Subarachnoid anaesthesia studies

All the haemodynamic values during the last 60 min of the pethidine maintenance infusion under subarachnoid anaesthesia were within 10% of the corresponding mean values during the

DISCUSSION

In awake unrestrained sheep, infusions of pethidine produced no significant haemodynamic changes, although cardiac output tended to increase. As

TABLE V. Effecu of subarachnoid anaesthesia (SA) and pethidine on blood flow. Values for cardiac output (CO), hepatic blood flow (HBF) and renal blood flow (RBF) in the control period before subarachnoid anaesthesia may be compared with values obtained during the last 60 min of the pethidine maintenance infusion during subarachnoid anaesthesia Before SA and pethidine iinfusion During !SA and pethidine infusion (4 Bets of determinations, 10 min apart over 30 min) (6 sets of determinations, 10 min apart over 60 min)

HBF

HBF

RBF

(litre min"')

(litre min"1)

(0.4)

1.35 (0.24)

0.76 (0.24)

0.74 ((0.01)

6.9 (0.8)

1.35 (0.23)

0.79 (0.02)

0.74 (0.02)

3.3 (03)

1.74 (0.14)

0.77 (0.02)

RBF

CO (litre min"')

(litre min"1)

(litre min"')

CO (litre min"1)

SD

4.4 (0.2)

1.49 (0.20)

0.74 (0.05)

SAii Mean SD

4.2 (0.4)

1.22 (0.33)

SAiii Mean SD

3.5 (0.6)

1.76 (0.01)

Study SAi Mean

5.3

GA OR SA AND PETHIDINE DISPOSITION mean arterial pressure did not change, this reflects a decrease in peripheral resistance, as is seen commonly in man. The changes in haemodynamic indices produced by general anaesthesia with halothane and the absence of such changes in association with subarachnoid anaesthesia (with fluid preload) are in accord with our previous report (Runciman, Mather et al., 1984b). Arterial concentrations of pethidine remained essentially unaltered with subarachnoid anaesthesia, but were doubled under general anaesthesia. Under general anaesthesia, hepatic clearances, extraction ratios and intrinsic clearances all were reduced, as were renal extraction ratios and clearances, whereas under subarachnoid anaesthesia there were no significant changes. This study adds to the increasing body of evidence that general anaesthesia with halothane may affect the disposition of drugs. For example, it has been reported also that the renal clearance of cefoxitin is reduced (Runciman et al., 1985), that the rate of ketamine and bupivacaine metabolism by rat hepatic tissue is reduced in vitro (White et al., 1976; Denson et al., 1982), that the half-lives of phenobarbitone and aminopyrine may be prolonged in vivo (Pearson, Bogan and Sanford, 1973; Wood and Wood, 1982), and that plasma concentrations of ketamine and pethidine may be increased (White et al., 1976; Steffey et al., 1977). Studies of the time course of such effects of halothane and other anaesthetic agents are in progress. A number of matters arising from these studies need further comment. First, the mean total body clearance of pethidine in the six control-drug studies ranged from 1.4 to more than 4 litre min"1. Similarly, high mean total body clearances of pethidine in the sheep can also be calculated from the data of others (Shier, Sprague and Dilts, 1973; Szeto et al., 1978). Although reports of the total body clearance of pethidine in man have varied (Mather and Meffin, 1978; Edwards et al., 1982), generally accepted mean values range from approximately 0.5 to 1 litre min"1. Second, summed hepatosplanchnic, pulmonary and renal clearance accounted for means of 54, 64 and 39% of the total body clearances in the control-drug, general anaesthesia and subarachnoid anaesthesia studies, respectively. Because the hepatosplanchnic extraction ratio approached unity, the hepatosplanchnic clearance of pethidine approached total hepatic blood flow. Renal, gastrointestinal and pulmonary clearances were

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small. Therefore, it can be calculated that extraction ratios approaching 50 % would have to exist for pethidine across regions supplied by the non-hepatosplanchnic non-renal components of the systemic circulation (for example that to limbs) to account for the difference between total body and summed regional clearances. Studies in progress in the sheep have confirmed these predictions for pethidine, as well as for other exogenous (Runciman et al., 1983) and endogenous substances (Robinson et al., 1984). Work is in progress to determine whether this discrepancy is the result of true extravisceral clearance, or of high affinity tissue binding (Upton, Runciman and Mather, 1986; Upton et al., 1986). While this may be a peculiarity of the species, there may be extravisceral clearance in man for a number of drugs of interest to the anaesthetist (Arthur et al., 1979; Mather et al., 1981; Adam et al., 1983). Third, since there was no appreciable prehepatic clearance of pethidine in the sheep, hepatosplanchnic clearance may be represented by hepatic clearance. Although the hepatic clearance of pethidine in the anaesthetized sheep remained high in absolute terms, the hepatic intrinsic clearance of pethidine was reduced to less than one-fifth of that in the awake sheep. As a consequence, there was a four-fold increase in the fraction transmitted through the liver. Since pethidine is cleared by metabolism, this provides indirect evidence that general anaesthesia with halothane may inhibit metabolic enzyme activity in vivo as well as in vitro. That the N-dealkylated metabolite, norpethidine, was present in hepatic venous blood during halothane anaesthesia, but not during control-drug or subarachnoid anaesthesia studies, suggests that the relative contributions of different routes of metabolism of pethidine or norpethidine may be altered by halothane anaesthesia. The conclusions from this study may have implications for both experimental pharmacology and anaesthetic practice. General anaesthesia with halothane, in contrast to subarachnoid anaesthesia, may be associated with higher than expected blood concentrations of pethidine as a result of the decrease in bloodflowthrough organs and regions of metabolism, a reduction in intrinsic clearance in some organs or regions, and possible changes in the relative contributions of different routes of metabolism. The common procedure of anesthetizing experimental animals during test procedures

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may produce unsuspected effects and results which cannot be extrapolated to awake animals. In species in which extravisceral clearance is important, pharmacokinetic analysis of venous data will yield entirely spurious results. ACKNOWLEDGEMENTS The authors gratefully acknowledge the technical assistance of Mr K. Parkin, and Mr C. F. McLean, the secretarial assistance o f M s L . Gregory, Mrs D. Brown and Mrs M. Wallace and the support of the National Health and Medical Research Council of Australia. REFERENCES Adam, H. K., Briggs, L. P., Bahar, M., Douglas, E. J., and Dundee, J. W. (1983). Pharmacokinetic evaluation of ICI 35868 in man. Br. J. Anaesth., 55, 97. Ahmad, A. B., Bennett, P. N., and Rowland, M. (1983). Models of hepatic drug clearance: discrimination between the "well stirred" and "parallel tube" models. J. Pharm. Pharmacol., 35, 219. Arthur, G. R., Scott, D. H. T., Boyes, R. N., and Scott, D. B. (1979). Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine. Br. J. Anaesth., 51, 481. Austin, K. L., Stapleton, J. V., and Mather, L. E. (1980). Relationship between blood meperidine concentrations and analgesic response: A preliminary report. Anesthesiology, 53, 460. (1981). Rate of formation of norpethidine from pethidine. Br. J. Anaesth., 53, 255. Branch, R. A. (1982). Drugs as indicators of hepatic function. Hepatology, 2, 97. Denson, D. D . , Myers, J. A., Walters, C , and Raj, P. R. (1982). Selective inhibition of the aromatic hydroxylation of bupivacaine by halothane. Anesthejiology, 57, A242. Edwards, D. J., Svenson, C. K., Visco, J. P., and Lalka, D. (1982). Clinical pharmacokinetics of pethidine (meperidine): 1982. Clin. Pharmacokinct., 7, 421. Greene, N. M. (1981). Physiology of Spinal Anesthesia. Baltimore: Williams and Williams. Jaffe, J. H., and Martin, W. R. (1980). Opioid analgesics and antagonists; in The Pharmacological Basis of Therapeutics (eds A. G. Goodman, L. S. Goodman and A. Gilman), New York: MacMillan. Lebaux, M. C. (1975). Sheep: a model for testing spinal and epidural anesthetic agents. Lab. Anim. Sci., 25, 629. Mather, L. E., and Meffin, P. J. (1978). Clinical pharmacokinetics of pethidine. Clin. Pharmacokinet., 3, 352. Seow, L. T., Roberts, J. G., Gourlay, G. K., and Cousins, M. J. (1981). Development of a model for integrated pharmacokinetic and pharmacodynamic studies of intravenous anasthetic agents: application to minaxolonc. Eur. J. Clin. Pharm., 19, 371. Tucker, G. T. (1974). Meperidine and other basic drugs: general method of their determination in plasma. J. Pharm. Set., 63, 306. Pearson, G. R., Bogan, J. A., and Sanford, J. (1973). An increase in the half-life of pentobarbitone with the

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