Clinical Pharmacokinetics 4: 433-448 0312-5963/79/1100-0433/$04.00/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Drug Kinetics and Hepatic Blood Flow Charles F. George Faculty of Medicine. University of Southampton

Summary

In adult man. liver blood flow amounts to roughly 100mi min-I for every 100g of liver (range 1.1 to I.B litres min - I) of which 70 to 75% is supplied via the portal vein. For certain drugs. when given intravenously. the liver represents the sale site of metabolic transformation and less than /0 % is eliminated unchanged by other routes. For these chemicals. the amount removed from the body in unit time depends on their rate of presentation to the healthy liver: thus. clearance depends on and approximates to hepatic blood flow. Such agents undergo extensive extraction at each circulation through the liver. the magnitude of this being determined largely by the activity of drug metabolising enzymes located therein. When such drugs are administered orally. there is extensive presystemic elimination which limits their bioavailability even though they are almost completely absorbed. Drugs which exhibit this type of pharmacokinetic pattern. include the antiarrhythmic agents lignocaine (lidocaine). lorcainide and verapamil; also lipid-soluble ~-adrenoceptor antagonists including alprenolol. labetalol. metoprolol. oxprenolol and propranolol. The opiate analgesics. morphine. pentazocine. pethidine (meperidine) and propoxyphene. as well as the antagonist. naloxone. show a similar pharmacokinetic pattern. Other examples include the eNS active compounds. imipramine. nortriptyline. chlormethiazole and methohexitone. Because the liver is their almost exclusive site of metabolic clearance it is possible to use one or more of these drugs to estimate hepatic blood flow in intact man: Hepatic blood flow and hence systemic clearance of such drugs is influenced by posture. exercise and perhaps by food. Hepatic blood flow decreases in old age and results in a prolongation in the half-lives of intravenously administered propranolol. lignocaine and chlormethiazole. In addition. there is evidence of diminished microsomal enzyme activity in the elderly. especially in the presen.ce of inducers of microsomal enzyme activity. leading to an increased bioavailabi/ity of these drugs after oral administration. Thyrotoxicosis is associated with an increased clearance of such drugs and a reduction in their steady-state plasma concentrations. whereas oppposite effects are seen in myxoedema. Similarly. heart failure leads to a reduction in their rates of elimination. either because of a diminished cardiac output or through an alteration in the distribution volume. Effects of hepatic disease are complex and vary according to the type and chronicity of liver pathology. the presence of hepatic failure and concurrent drug therapy. In general. acute viral hepatitis

Drug Kinetics and Hepatic Blood Flow

434

produces little change in drug pharmacokinetics whereas chronic liver disease (particularly cirrhosis) leads to a prolongation of their hal/-lives and diminished systemic clearances. The changes are most prominent after oral administration of such drugs and are manifest as an increased bioavailabillty. Concurrenrdrug therapy can affect the pharmacokinetics of drugs like propranolol eilher by altering hepatic bloodflow - catecholamines and glucagon for example - or by changing the extraction ratio through an effect on enzyme activity in the liver.

The liver is the largest solid organ in the body, weighing 1.2 to 1.8kg: functionally, it is bilobed with separate afferent and efferent blood vessels, each of which subdivides into 4 segmental branches. Arterial blood is supplied to the liver by the hepatic artery, which is responsible for 25 to 30% of the total afferent blood flow and some 50 % of the oxygen supply (Dawson, 1979). The remaining 70-75% of hepatic blood flow is supplied via the portal vein, which is formed from the superior mesenteric and splenic veins behind the head of the pancreas. The efferent vessels of the liver are the hepatic veins, which drain directly into the inferior vena cava. Between the afferent and efferent vessels, blood circulates through special capillaries called sinusoids, the walls of which consist of endothelial cells and phagocytes, known as Kupffer cells. Although the majority of blood from the hepatic artery and portal vein passes through the sinusoids before reaching the hepatic veins, there are arteriolovenular communications at capillary level which can give rise to shunting of blood (and hence influence measurements of hepatic blood flow).

J. Measurement of Hepatic Blood Flow Although both direct and indirect methods have been described, only the latter are practicable for use in healthy man, because the former involve surgical intervention. The indirect methods, include single injection and clearance techniques, fractiorult distribu-

tion studies and washout of inert gases. Each of these has inherent advantages and limitations (recently reviewed by Ohnhaus, 1979), which should be remembered when considering the figures given later in this review.

1.1 Single Injection Method The fate of injected colloids such as 32p chromium phosphate, 198 Au gold and 11II-labelled serum albumin can be studied by sampling from peripheral veins or by counting externally with a scintillation collimator or gamma camera. These substances are sequestered by the Kupffer cells (and other reticuloendothelial cells) and their clearance can be used to estimate hepatic blood flow (Q). Q = k e • BV

(Eq. I)

where ke is the colloid disappearance rate constant and BV the blood volume. However, this technique may overestimate liver blood flow because of the initial rapid distribution of colloid to the tissues and extrahepatic removal. A further potential problem is nonuniformity of the colloid particle size.

1.2 Clearance Techniques The constant infusioll method was first described by Bradley et al. (I 945). Hepatic blood flow (Q) is calculated by using a constant infusion of dye - tra-

435

Drug Kinetics and Hepatic Blood Flow

ditionally either indocyanine green (lCG) or bromsulphthalein (BSP) - and measuring its extraction across the liver. Thus: Q

rate of dye removal arterial - hepatic vein dye diff.

haematocrit (Eq.2)

When the arterial blood dye concentration is constant the rate of removal equals the rate of infusion. However, because BSP undergoes enterohepatic recirculation (Lorber et aI., 1953), ICG is the preferred indicator. Nevertheless, invasion of the patient is necessary to provide both peripheral arterial and hepatic venous samples. In addition, the concentration of ICG in samples is subject to error because extraction is dependent upon the position of the catheter. When the latter is deeply inserted, comparatively low extraction ratios (E) may be obtained (Sapirstein and Reininger, 1956).

1.3 Other Methods Fractional distribution of blood flow can be measured by using tagged microspheres. However, this technique requires removal of the tissues and subsequent scintillation counting and is not, therefore, appropriate for use in man. More recently an inert gas washout technique using either 85krypton or IJJxenon has been described and refined by Ohnhaus et al. (J 979). Although noninvasive, it requires a computer system to process the data acquired and assumes that hepatic arterial and portal venous contributions to Q remain 30 and 70 % respectively (which may be incorrect). Alternative pharmacological approaches to the measurement of hepatic blood flow are discussed below.

2. Values of Hepatic Blood Flow Values of hepatic blood flow in man, obtained by several different techniques, have been summarised by Grayson and Mendel (J 965) and range from \.09

to 1. 7 9 litres min - I. Assuming an average liver weight of l.5kg, hepatic blood flow is similar to that of most laboratory animals at 72.5 to 119.0ml min-I for every 100g of liver. However, there is considerable variation with age, posture etc. which is discussed later in this review.

3. Drug Kinetics and Hepatic Blood Flow 3. I Theoretical Considerations 3.1.1 Pharmacokinetics after Intravenous Administration

Consider the fate of a drug administered intravenously, for which the liver represents the sole or major site of metabolic transformation (and less than I 0 % of which is eliminated unchanged by other routes). In this situation, the amount of drug removed from the body in unit time must depend on the rate of presentation of drug to the liver. The amount of drug carried to the organ will be determined by its distribution volume (and hence protein binding) and hepatic blood flow. Clearance (the volume of blood from which drug is totally removed in unit time) depends on the overall ability of the liver to bind and metabolise the drug which is reflected in the extraction ratio (E). Thus: E

A-H

=--

H

(Eq.3)

where A is the concentration of drug in afferent blood (arterial and portal venous) and H the concentration in hepatic venous blood. However, E reflects several factors, which include the relative affinity of plasma and hepatic proteins to bind it, the concentration gradient between blood and liver and the activity of drug metabolising enzymes. For drugs with high values of E, their half-lives must reflect hepatic blood flow and their clearances, which are perfusion limited (Rowland et al., 1973), may approach Q. In addition, clearance will increase in proportion to any rise in Q (Wilkinson and Shand, 1975). Although Q itself may influence E (fig. J)

436

Drug Kinetics and Hepatic Blood Row

changes in E are small within the physiological range ofQ.

3.1.2 Pharmacokinetics After Oral Administration By using drugs which have been radio-labelled with either JH or 14C it has proved possible to demonstrate that many, such as propranolol, which are lipid-soluble are completely absorbed from the gastrointestinal tract since virtually all the radioactive material can be recovered in urine (Paterson et al., 1970). Despite this, systemic bioavailability measured by comparing the area under the plasma concentration-time curves for oral and intravenous administration (AUC o( AUCiv; - henceforth designated, F) corrected for dose is less than unity. If intestinal absorption is complete yet F is small, by implication there must be considerable presystemic metabolism in either the gut wall or liver. It is not possible to state the relative contribution of the 2 sites to low values of F without measuring E across the liver, or estimating biotransformation in the intestine using a technique such as that described by George et al. (I 974). In addition, observed values of F may be higher than predicted from measurements of E made following intravenous administration due to the fact that almost all of the drug absorbed from the intestine passes through the liver in high concentration (compared with that seen after intravenous administration) and may saturate the hepatic drug metabolising enzymes.

3.2 Drugs Showing Hepatic Blood Flow Dependent Kinetics To date, the best documented examples of drugs showing kinetics which are dependent on hepatic blood flow are drawn from a small number of therapeutic groups; notably drugs acting on the cardiovascular and nervous systems. Examples of the former include the antiarrhythmic agents lignocaine (lidocaine) and lorcainide as well as severallipid-soluble members of the ~-adrenoceptor antagonist series. Analgesics, hypnotics and tricyclic antidepressants comprise the remainder. Regrettably, most of the data

are incomplete, especially direct measurements of E. Nevertheless, from the theoretical considerations discussed earlier it follows that drugs which are well absorbed, undergo extensive biotransformation and have low values of F, must exhibit liver blood flow dependent kinetics. Individual values of these are given in table I.

3.3 The Use of Drugs to Estimate Hepatic Blood Flow Theoretically, by using drugs whose absorption from the gastrointestinal tract is virtually complete (and elimination unchanged is negligible) it is possible to estimate Q from the pharmacokinetic data obtained for both oral and intravenous dosing. The information required is as follows: firstly, F which is obtained in the following manner: Div

F

x

AUC o

Alternatively, F = I - E

(Eq.4)

(Eq.5)

Secondly, clearance: CI. IV

D·

=_IV_

AUCiv

(Eq.6)

But, according to the Pick principle: consumption

Flow

arteriovenous difference

(Eq.7)

Thus:

Q

Cliv E

(Eq.8)

and I - E = F (see above). This principle has been used in a number of studies emanating from Nashville (Kornhauser et aI., 1978; Wood et al., 1978) and figures for hepatic blood flow obtained using this technique are similar to those recorded using other methods. Nevertheless, this particular technique assumes that there is no ex-

437

Drug Kinetics and Hepatic Blood Flow

(1951) using the BSP clearance technique. On tilting from horizontal to 75° head up, hepatic blood flow fell by 35% from 995ml min-I per M2, despite a fall in mean systemic blood pressure of only I mm Hg. In addition, Wade et al. (I 956) showed that splanchnic blood flow fell by an average of 355ml min-I in 5 normal subjects during light exercise, supine. Despite the magnitude of these changes scant attention has been paid to them in some published pharmacokinetic studies.

100

~ 00

580

660

Liver blood flow (mil min)

740

Fig. 1. The

relationship between the extraction of propranolol across the liver and hepatic blood flow. Despite the significant correlation between these 2 parameters (R = 0.70; p = 0.05) in this anaesthetised dog, the extraction ratio (E) differs little although hepatic blood flow varied between 513 and 684ml min -'.

trahepatic metabolism or elimination of the 'marker' drug. Available evidence suggests these conditions are not met, since there is a discrepancy between the total and hepatic clearance of both lignocaine (Stenson et al., 197 J) and propranolol (George et al., 1976). However, this does not necessarily limit the use of the technique if extrahepatic clearance has been quantified and found to be small. Also, if it is identical for oral and intravenously administered drug then it can be ignored.

4. Physiological Changes in Hepatic Blood Flow Likely to Affect Drug Kinetics Humoral influences, posture, food and age are among the factors which are known to influence hepatic blood flow. 4.1 Posture The effect of postural change on liver blood flow has been investigated in man by Culbertson et al.

4.2 Food Food may also influence portal and thus total hepatic blood flow. Using a computer simulation, McLean et al. (I978) have suggested that increased splanchnic blood flow after a meal might account for the observed effects of food on the bioavailability of metoprolol and propranolol reported by Melander and colleagues (I 977). However, this suggestion remains unproven and does not take account of possible food-induced alterations in the rate of gastric emptying, a parameter which is known to affect plasma propranolol concentrations (Castleden et al., 1978).

4.3 Older Age There are several published studies showing a decline in cardiac output and hepatic blood flow in old age (Brandfonbrener et aI., 1955; Sherlock et al., 1950). In view of this, it is not surprising that Castleden and George (I979) found a prolongation of the half-life of intravenously administered propranolol (0.15mg kg-I) to 254 ± 51.9min in a group of 8 elderly subjects whose average age was 78 years compared with a value of 152 ± 1O.3min in 7 young normals with an average age of 29. Similarly, clearance was significantly lower in the elderly group averaging 7.8 ± 1. 3ml kg - I min - I, compared with 13.2 ± l.4ml kg-I min -I. Slightly different results were obtained by the Nashville group (Wood et al .• 1978) when ']H-labelled propranolol was given intra-

Dose

R'

labetalol

Alprenolol

~-Adrenoceptor

Verapamil

Lorcainide

100200mg 3H labetalol 0.5mg kg-' 200mg l00mg l00mg 200mg

antagonists lOmg l00mg

0

0

iv 12 6 6

7N

iv

0

2

4N

3P

3P

5N 6P 2N 2N 2P 2P

3N

4N

250± 144n9 ml-'h 267 ± 118ng ml-'h 1.31 ±0.61p9 ml-'h 0.46±0.25pg ml-'h 0.52 ± 0.29)19 ml-'h

190±8ng ml-'h 130± 55ng ml-'h

199.3ng ml- 1h ( 148.8-228.8) ~54.2ng ml-'h (70.5-249.4)

1.5 ± 0.6l min-'

0.42l min-'

0.73-1.98l min - ,

1.49 ± 0.26l min - , 1.60±0.36l min-'

38 (11-86) 28 (19-49)

33±8

10-22

13.5 (7-20) 4.5 50.0 (35-65)

2.0

>95%

>98%

Homeida et al. (1978) McNeill et at (1979)

Martin et al. (1976)

Ablad et al. (1974)

Schomerus et al. (1976)

Klotz et al. (1978)

Tschanz et al. (1977)

Nation et al. (1977)

Stenson et al. (1971) Thomson et al. (1971)

20ml kg-'min-' 10ml kg-'min-' (0.70l min-') 7.6ml kg-'min-' (0.54h min - ') 1O.1ml kg-'min-' 98.2%

Extent Reference of metab.

17P 10N

33.6 ± 11.6

F%

Boyes et al. (1971)

CI

1.56l min-'

1.99pg ml-'h 0.64pg ml-'h

AUC

5N

64.9

No. E% studied

0

0

iv

0

'''C

80mg

iv

0

0

0

0

iv iv

10mg 14C

l00mg l00mg 100mg 150mg l00mg 200mg

iv

l00mg 200mg

0

iv

50mg

Antiarrhythmic drugs iv lignocaine 250mg 50mg /lidocaine} bolus + 4ClJJg kg - 'min -, iv 50mg iv

Drug

Table I. Pharmacokinetic parameters obtainuf subjects with normal hepatic function for drugs which exhibit hepatic blood flow limited dependent kinetics

~

::l

... 00

w

:;:

EP

c.

0

0-

OJ

o·

~

"C

::l

c. :r CD

.,'"

1r

l~

10mg 20mg 20mg 40mg 80mg 160mg

1mg 14C labelled 40mg 20mg 10mg

Oxprenolol

Propranolol

Morphine

5.75mgJ M2

Opiate analgesics and antagonists

0.27mg kg-' (+ )-plus 80,.,g kg-'h-'

80mg tds plus iv 3H 0.27mg kg-' (+ )-plus 80)1g kg- 'h-'

80mg 40mg(+)

5mg 10mg 15mg 20mg 20mg 50mg 100mg 5mg 3H-labelled

Metoprolol

iv

0

iv

0

6N

7P

12P

iv

iv

15N

0

iv

6N

3P 2P 6N

iv iv

0

3P

6N

0

iv

6N

iv

5N

5N

0

0,

5N

iv

79 ±5.3

74 ±3.5

64.0 ± 7.7

455 ± 67ng ml-'h 904± 176 330± 201 792 ± 237 1468±517 2627± 757

0.9l min-' ±0.27 0.9l min-' ±0.27

1.08l min-' ±0.09

5.67ml kg-'min-' 5.70ml kg-'min-'

36 (22-56)

17

38.5 45.2 41.7 37.5

31 41 46

Mason and Winer (1976)

Regardh et al. (1974)

>91%

Brunk and Delle (1974)

Weiss et al. (1978)

Kornhauser et al. (1978)

Branch et al. (1976)

Shand and Rangno (1972)

'Almost Paterson et al. (1970) complete'

100%

Johnsson et al. (1975)

0

2

w

CD

~

:E

5"

"

8.

5"

ttl

1;-

"0

CD

.,...

:I:

::l 0.

.,'"

1;-

S

5·

'"

co

125"g

l~g

Naloxone

e

50mg 50mg

3mg kg-' over hour

192mg> 192mg> 1.20-2.25g 384mg>

= Estimated.

Symbols 1 R = Route. > = Base.

Methohexitone

Hypnotics Chlormethiazole

Nortriptyline

35-50mg

0

50mg 60mg 130mg 195mg

Propoxyphene

Antidepressants Imipramine

iv

0.8mg kg-' 50mg

Pethidine (meperidine)

iv

0

iv

0

iv

0

iv

0

ivand

0

0

0

iv

iv iv

0

iv

R'

24mg> 89mg>

Dose

Pentazocine

Drug

Table I. (continued)

4N

6N 1N

6N

6P

3N lP

1N

7N

8N

8N 4N

4N 4N

No. E% studied

2.48 ± 0.37"g ml-'h 0.29 ± O.17"g ml-'h 19.5± 6.10mg L-'h

1905±577"g L-'h 956 ± 282"g L - 'h

0.773(e) "g ml"h 0.230 (e) 0.658(e) 1.054(e)

AUC

0.83L min-' (0.66-1.00) 12.1ml kg-'min-'

23.0±4.1ml kg-'min-'

18.2 ± 2.9ml kg' 'min-'

0.53 ± 0.12L min-'

1.05 ± 0.44L min - , (17.1ml kg-'min-')

1.77L min-'

1.32 ± 0.38L min - , 1.02 ± 0.40L min - , (14± 5ml kg-'min-')

CI

11.8 ± 7.1 15

50.5± 4.6

47.3±21.4 (29-77)

23 33 35

35-70

F%

99%

>95%

>99%

Almost 100%

100%

84.6 (76-91)

Breimer (1976)

Mooreet al. (1975)

Pentikainen et al. (1978)

Gram and Overa (1975)

Gram and Christiansen (1975)

Fishman et al. (1973)

Wolen et al. (1971)

Klotz et al. (1974) Mather et al. (1975)

Beckett et al. (1970)

Extent Reference of metab.

CD

t

o

::E

~

c.

0 0

!;!;!

!!! C;.

'0

:I:

C.

:l

III

en

:r ~ c;.

I~

441

Drug Kinetics and Hepatic Blood Flow

venously to a younger group of subjects who were already receiving regular oral doses of propranolol. Under these circumstances, both E and clearance are likely to be more dependent upon the metabolic capacity of the liver than following a single intravenous dose. Possibly because of this no change in propranolol clearance was seen with increasing age (up to 72 years) in non-smokers. However, in smokers of cigarettes, propranolol clearance was shown to diminish with increasing age. Clearly, with oral dosing, bioavailability is inversely related to clearance by intrinsic metabolism. Reduction in the latter by old age is the likely explanation for the higher value of F - 54.6 % compared with 30.1 % in young normals - found by Castleden and George (I 979) after a 40mg oral dose. To date, few pharmacokinetic studies have been undertaken in old age for other drugs which exhibit high values of E, but lignocaine and chlormethiazole are exceptions. Nation et al. (I 977) reported clearances of 556± 150ml min-I (8.1 ± 1.9ml kg-I min-I) in 6 patients with an average age of 65 years. Although these values did not differ significantly from those obtained in 4 normal subjects (see table I) they are substantially lower than those obtained in most other studies of lignocaine pharmacokinetics. Significant reductions in the clearance of chlormethiazole have been demonstrated in old age. In 8 healthy subjects with an average age of75.3 years the plasma clearance was 16.1 ± 5.0ml kg-I min-I (Nation et aI., 1976) compared with values of 23.0 ± 4.1 ~btained in 6 subjects with a mean age of 22.7 years studied in the same laboratories by Moore et al. (I 975).

5. Drug Kinetics in Disease and Altered Hepatic Blood Flow Disease states may affect the pharmacokinetics of drugs with high values of E in one of several ways. Firstly, their distribution volumes may be altered; in some situations by abnormal (increased or decreased) protein binding. Alternatively, regional cardiac out-

put can be affected by disease, or effective Q reduced by shunting. Finally, enzyme activity may be reduced in disease of the liver and result in increased values ofF. The precise contribution of these mechanisms to alterations produced in various diseases remains to be elucidated. This review confines itself firstly, to a discussion of the situations where Q is either known or might be expected to be reduced by disease; secondly, to other changes due to hepatic disease; and finally, to the effects of concurrent drug therapy. For a discussion of other disease states in which pharmacokinetics of flow limited drugs such as propranolol are known to be abnormal, the reader is referred to the recent review by Routledge and Shand (I 979).

5. I Thyroid Disease Cardiac output (and thus hepatic blood floW) is reduced in hypothyroidism and increased in thyrotoxicosis. These changes may account for the variation in steady-state plasma concentrations of propranolol reported by Feely et al. (I978) and the increased clearance of the drug in thyrotoxicosis shown by Riddell et al. (I 979).

5.2 Cardiac Failure There are two main changes in heart failure which lead to alterations in drug pharmacokinetics: reduced cardiac output (and hence Q) and alteration in distribution volumes (Thomson et al., 1973; lIett et aI., 1979), both of which may cause a reduction in the rate of elimination of drugs which have high hepatic extraction ratios. Most studies published to date relate to lignocaine. In the monkey, a decrease in cardiac output associated with blood loss leads to a prolongation of the lignocaine half-life and diminished clearance (Benowitz et aI., I 974). In man, Thomson et al. (I 971) reported clearance values of 358 ± 147ml min -I (5.0 ± 2.5ml kg-I min-I) following intravenous administration of

Dose

5mg

0

2OOm9

labetalol

iv

l00mg 200mg

0

0

0.5mg kg-' iv

~-Adrenoceptor antagonists

Verapamil

iv

0

iv

0

400mg

100mg 200mg 100mg

iv

0

iv

R'

1mgkg-'

Antiarrhythmic drugs Lignocaine 50mg (lidocaine) 400mg

Drug

10(9 cirrhotics; 1CAH) 4 6(9 cirrhotics; 1 CAH)

4 (cirrhotics) 1 (fatty liver)

3 (CAH)

16 (cirrhotics) 3 (CAH) 2 (others) 6 (cirrhotics)

6 (AVH) In recovery

8 (alcoholic liver dis) 1 (CAH)

No. studied E%

0.311 ± 0.147119 ml-'h

2.36± 0.85}19 ml-'h

4.97 ± 0.80 3.15± O.S8}1g ml-'h 4.83± 1.01

AUC

0.50lmin-'

0.53±0.17ml kg-'min-'

5.56 ± 0.66ml kg-'min-'

5.82 ± 1.34ml kg - 'min-'

20.0 ± 3.9ml kg -'min -,

13.0 ± 3.9ml kg - 'min - ,

0.37 ± 0.18l min-'

CI

63±22

49.1 ± 15.2

64.6±4.2

F%

2.83 ± 1.26

13.6±8.7

6.6± 1.1

Homeida et al. (1978)

Rietbrock et al. (1979)

Tschanz et al. (1977)

Forrest et al. ( 1977)

Williams et al. (1976)

Adjepon-Yamoah et al. (1974)

19.1

2.67 (1.1-7.2) 1.5 (1.2-3.5)

Thomson at al. (1971)

Reference

5.72± 3.90

(h)

t'/2

Table II. Pharmacokinetic parameters obtained in patients with hepatic diseufor drugs which exhibit hepatic blood flow limited kinetics

::l

-l> -l>

'"

:!:

0"

"TI

~c.

!!1 n·

CD "0

:I:

a.

III

'"

s· ~ n·

I~

iv

5.05 ± 2.29)1g ml- 'h

8 cirrhotics

0

Symbols 1 R = Route. * = Base. AVH = Acute viral hepatitis. CAH = Chronic active hepatitis.

3.73± 1.78)1gml-'h

73±8

41 ± 17

8 cirrhotics

10 cirrhotics 14AVH 5 in recovery 8 cirrhotics

8 cirrhotics

12 cirrhotics 6CAH 2 others 14 cirrhotics 6 fibrosis 7 cirrhotics

iv

0

0.8mg kg -, iv

0.8mg kg -, iv 0.8mg kg -, iv

0

O.4mg kg-' iv

0

80mg tds

+ 3H

(+)-

O.4mgkg-' iv

40mgl +)- iv

Hypnotics / sedatives Chlorme192mg* thiazole 192mg*

Pethidine (meperidine)

Analgesics Pentazocine

Propranolol

Table II. (continued)

12.8 ± 4.8ml kg - 'min - ,

136%

0.66 ± 0.29L min - , 0.65 ± 28L min-'

146%

18 ± 8mlkg-'min-' 0.58±0.37

8± 5ml kg-'min-'

0.46L min-' (0.14-1.09)

> 100

87

69

54± 16

8.7±4.0

7.04±0.92 6.99± 2.74 3.25±0.8

11.2±8.5

15.6 (2.8-35.4)

Pentikainen et al. (1978)

Blaschke et al. ( 1978)

Klotz et al. (1974) McHorse et al. (1975)

Blaschke et al. (1978)

Wood et al. (1978)

Pessayre et al. (1978)

Branch et al. (1976)

0

2

~ ~

w

~

0-

"

8.

0-

OJ

n·

~

CD "0

J:

:::l Co

'"'"

S ,;-

"5·

co

Drug Kinetics and Hepatic Blood Flow

444

50mg and an infusion of I mg min - 1 to 7 patients with heart failure. Similarly, Prescott et al. (1976) found a significant prolongation of the half-life of lignocaine to 10.2 ± 5.3h in 7 patients with heart failure after myocardial infarction compared with 4.3 ± 2.1 h in those without. Finally, Nation et al. (1977) have reported half-lives of 6.0 ± 6.0h in 13 patients with cardiac disease.

5.3 Hepatic Disease The pharmacokinetic changes which can occur in hepatic disease have been the subject of several reviews in the past few years (Wilkinson and Shand, 1975; Branch and Shand, 1976; Wilkinson and Schenker, 1976; Blaschke, 1977; Wood et al., 1978; George and Watt, 1979). These changes vary accord-

Hepatic total 14C Arterial total 14C

E ..s

d, 100 Arterial free propranolol (extracted)

~ :~ 1:)

'"

o is

~

m

§

Hepatic free propranolol (extracted)

'tl

c:

'"

'0 '0 c: ~

c. c.

e

,,

10

1,'1

.,

c: .o

I

~

., o

E

I

I

c:

o

o

'"

Desmethylimipramine

E

"' ~

1

a

20

40

60

80

100

120

140

Time (minutes) Fig. 2. The effect of desmethylimipramine on the pharmacokinetics of propranolol after intravenous dosing followed by continuous infusion. In this anaesthetised dog, propranolol was given as an intravenous bolus of 0.3mg kg -, of the racemate, followed by continuous infusion of half this amount each hour. Blood was collected from the aorta and a hepatic vein to estimate . concentration of propranolol in systemic blood (X) and hepatic venous blood ( I ). In addition, the dog was administered 14C-propranolol in a total dose of 22~Ci to allow the estimation of metabolites in aortic (0) and hepatic venous blood ( .). After 53min the animal received an intraportal venous dose of desmethylimipramine (50mg). Following this there was an immediate reduction in the extraction ratio of propranolol across the liver.

445

Drug Kinetics and Hepatic Blood Flow

ing to the type and chronicity of the liver pathology, serum albumin concentration, the presence or absence of jaundice, co-existent renal failure and concurrent drug therapy. Space does not permit a complete review of these, but the following conclusions may be drawn. Firstly, hepatic disease leads to an increased bioavailability and decreased systemic clearance after oral administration of drugs which undergo high clearance at the first pass; as reviewed by Blaschke and Rubin (J 979) elsewhere in this issue. Secondly, distribution volumes tend to be increased in patients with chronic hepatic disease, especially in the presence of reduced serum albumin concentrations. Thirdly, protein binding is altered in patients who are hypoalbuminaemic, jaundiced and/or uraemic, leading with highly albumin-bound drugs to increased pharmacological and therapeutic effects if the plasma concentration of unbound drug is increased. Fourthly, elimination half-lives and metabolic clearances show little change in acute viral hepatitis but considerable alterations occur in those patients with decompensated chronic liver disease. These are accompanied by a reduction in serum albumin concentrations and reduced clearances ofICG, and sometimes by portosystemic encephalopathy. Individual data are given in table II.

6. Drug Interactions Concurrent medical therapy given with those flow limited drugs discussed earlier can influence their pharmacokinetics in two ways: by increasing Q with I) Haemodynamic catecholamines or glucagon or reducing it with propranolol; see reviews by Nies et al. (I974, 1976). 2) By altering E - either by increasing the metabolic capacity of the liver (Branch et aI., 1974): alternatively, by altering the binding of propranolol (Evans et ai., 1973) or by inhibition of drug metabolism (Shand and Oates, 197 J). No systematic studies have been published on this last form of interaction but an example ofthe in vivo effects of tricyclic antidepressants is given in figure 2.

7. Other Drugs Which May Show High First-pass Hepatic Metabolism Only drugs for which good evidence of extensive first-pass metabolism in the liver exists have been considered in this review. However, there are a number of other potential candidates which include paracetamol (acetaminophen), for which there is evidence of a 25 % first-pass hepatic metabolism after intraduodenal administration in the dog (George and Cohen, unpublished). Also, after oral administration in man its bioavailability is 63 % at 500mg doses and 89 % at Ig doses (Rawlins et ai., 1977). The vasodilator, hydrallazine, is another candidate (Talseth, 1976), the pharmacokinetics of which were reviewed in the journal by Talseth (1977). Definite conclusions on this drug must await the results of further studies and resolution of uncertainties concerning the reliability of the assay techniques. Finally, the antiemetic compound, metoc\opramide, shows a high degree of first-pass metabolism which leads to a variable and incomplete bioavailability after oral administration (Bateman, personal communication). Blaschke and Rubin (J 979) mention other drugs which have been suspected of showing high hepatic first-pass metabolism. Prazosin, an a-adrenoceptor antagonist used in hypertension and heart failure, is almost certainly subject to extensive first-pass metabolism in the liver and the half-life is prolonged in patients with congestive heart failure (Jaillon et ai., 1979).

Acknowledgements I wish to thank Dr D.G. Shand for his advice and Mrs F.D. Lowman who typed the manuscript.

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Author's address: Prof. C.F. GeorgI!, Clinical Pharmacology, University of Southampton, Medical and Biological Sciences Building, Bassett Crescent Ea~t, SOlIlhamplOl/ S09 3TU (England).