Br. J. clin. Pharmac. (1976), 3, 907-913

THE RELATIONSHIP BETWEEN LIVER VOLUME, ANTIPYRINE CLEARANCE AND INDOCYANINE GREEN CLEARANCE BEFORE AND AFTER PHENOBARBITONE ADMINISTRATION IN MAN C.J.C. ROBERTS, L. JACKSON, M. HALLIWELL & R.A. BRANCH* Departments of Medicine and Pharmacology, University of Bristol and Department of Medical Physics, Bristol General Hospital, Bristol

I Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. 2 The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. 3 Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. 4 Phenobarbitone administration increased the clearance of antipyrine significantly by 90 ± 14% but there was no significant change in indocyanine green clearance or liver volume. 5 After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. 6 These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.

Introduction

The elimination of antipyrine and indocyanine green is determined by different rate limiting factors. Antipyrine is a soluble drug which is rapidly and completely absorbed when administered orally. It does not bind to plasma or tissue proteins and is distributed similarly to the body water. As it is lipid soluble it is not excreted by the kidney but undergoes metabolism by the microsomal enzymes in the liver prior to elimination (Brodie & Axelrod, 1950). The rate of metabolism is slow so that hepatic extraction is low and hepatic clearance is less than 2% of liver blood flow (LBF) and thus clearance is independent of changes in LBF (Branch, Shand, Wilkinson & Nies, 1974). In contrast indocyanine green is a dye which is almost completely protein bound and is rapidly eliminated by the liver being actively transported into bile without undergoing metabolic transformation (Cherrick, Stein, Leevy & Davidson, 1960). The hepatic extraction ratio is high. Consequently the hepatic clearance is high * Present address: Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, U.S.A.

55

and is limited by LBF (Branch, Shand & Nies, 1973) and has been used to measure LBF (Caesar, Shaldon, Chiandussi, Guevara & Sherlock, 1961). In spite of the differences in the rate limiting factors in the elimination of these two drugs a strong positive correlation has been observed between the clearances of these two agents both in normal subjects and in patients with chronic liver disease when it was postulated that the more fundamental common rate-limiting factor in their elimination was the 'functional hepatic parenchymal mass' (Branch, James & Read, 1975). This hypothesis would suggest that variation in the clearances of either drug between subjects is dependent on the 'functional hepatic parenchymal mass' which in normal subjects would approximate to liver volume. The objective of this study was to develop a method for measuring liver volume using an ultrasound technique and to investigate whether differences between subjects in the clearance of these two drugs could be explained by differences in liver volume. Furthermore microsomal enzyme induction by phenobarbitone is known to be accompanied by

908

C.J.C. ROBERTS, L. JACKSON, M. HALLIWELL & R.A. BRANCH

an increase in hepatic mass and LBF in the rat (Ohnhaus, Thorgeirsson, Davies & Breckenridge, 1971) and rhesus monkey (Branch et al., 1974) but its influence on hepatic size has not been previously determined in man. This study has investigated the influence of phenobarbitone on liver volume and the disposition of antipyrine and indocyanine green in man and has examined the interrelationships between these parameters after enzyme induction.

Method

Three female and seven male healthy subjects aged 20-30 years volunteered to take part in the study which had been approved by an ethical committee. No drugs or oral contraceptives were being taken and alcohol was limited to one pint of beer per day. Each subject received phenobarbitone 120 mg orally at night plus 30 mg twice daily for 3 weeks. Liver volume was measured three times before and once after phenobarbitone. Indocyanine green clearance, antipyrine clearance, serum bilirubin, alkaline phosphatase, aspartate transaminase, albumin and globulin were measured before and after phenobarbitone administration. Plasma phenobarbitone levels were measured at the end of 3 weeks of drug administration. Liver volumes were determined by an ultrasonic scanning technique similar to those of Rasmussen (1972) and Tolbert, Zagzebski, Banjavic & Wiley (1974). Serial transverse scans were recorded at 1 cm intervals from the inferior limit of the liver to the upper limit at which liver outline could be clearly visualised. Liver edge above this level was delineated by serial longitudinal scans in the sagittal plane. Scans were performed during maximum inspiration with the subject supine. Scans were photographed and liver outline transcribed to paper. The whole areas of the liver on the transverse scans and the appropriate areas on the longitudinal scans were measured using a computer fitted with a graphic tracing device. Liver volume was derived as the sum of all the areas measured multiplied by the magnification factor used. After an overnight fast and removal of blood for haematocrit and blank and standard curve measurements, indocyanine green (0.5 mg/kg body weight) was administered intravenously. Venous blood samples were taken from the opposite arm through an indwelling catheter at 3 min intervals for 21 minutes. Plasma concentrations were measured within 2 h of administration of the dye by the method of Caesar et al. (1961). Antipyrine (1200 mg) was administered orally as a freshly prepared solution by dissolving

crystalline antipyrine in water (50 ml). Venous sampling was performed through an indwelling catheter. Samples were taken at 5, 10, 15, 20, 30, 45 min and 1, 2, 3, 5,7,9, 15 and 24 h after drug administration. Antipyrine was assayed by the spectrophotometric method of Brodie, Axelrod, Soberman & Levy (1949).

Calculations The clearances of antipyrine and indocyanine green were estimated from the area under the plasma concentration curve (AUC) extrapolated to infinity as clearance = Dose/AUC. The plasma half-life (TL.) was estimated by least squares regression analysis of the log concentration - time profile. Absorption of antipyrine was shown to be rapid, mean time to peak plasma level being 39 ± 8 min (mean ± s.e. mean). Assuming complete absorption of antipyrine and a monoexponential elimination of indocyanine green, the clearance of each drug was calculated from Dose 0.693 x Clearance = T2 Cpo where Cp0 = plasma concentration back extrapolated to the time of drug administration. Plasma indocyanine green clearance was corrected to whole blood clearance using the haematocrit. The blood to plasma ratio for antipyrine was assumed to approximate to unity (Branch et al., 1974) and thus blood clearance equated with plasma clearance. Results Liver volume measurement The technique for measuring liver volume was found to yield reproducible results. The mean coefficient of variation for the results of the three base line scans was 5.7%. The values obtained ranged between 1.8% and 2.4% of total body weight with a mean of 2.1% (Table 1). Liver volume correlated with body weight (r = +0.81, P < 0.01). Liver volume, antipyrine clearance and indocyanine green clearance before phenobarbitone administration One subject had a very high initial antipyrine clearance (80 ml/min), being 5 ml/min greater than two standard deviations above the mean for the whole group. This increased only minimally after phenobarbitone suggesting that this subject had maximal enzyme induction at the start of the study but no obvious cause was evident. The antipyrine clearance of the other nine subjects

PHENOBARBITONE, LIVER VOLUME AND DRUG DISPOSITION

I-

Ea

a)

2000

0

u

C,

a)0 c

909

0

a2)

a)

60

I

°: .C 1500-

0

C

a)

0

a)

c 40

0

a) -1000

0

*

0

0._ C


Z

0

.

0

0

500

1000

150(O

c

2000

50CD

1000

1500

2000

Liver volume (ml) Figure 1 The relationships (a) between liver volume and antipyrine clearance (nine healthy subjects) and (b) between liver volume and indocyanine green clearance (ten healthy subjects) before enzyme induction. Open circles identify subjects with an apparently low indocyanine green clearance for their liver volume. For (a) r = +0.69, P < 0.05.

correlated with liver volume (r = +0.69, P < 0.05) (Figure 1). There was no significant correlation between the clearance of indocyanine green and liver volume. However, the initial indocyanine green clearances in seven subjects approximated to 1 ml/min per ml of liver, whilst in the other three subjects the indocyanine green clearance per unit volume of liver was lower (Figure 1).

Influence of phenobarbitone administration The plasma phenobarbitone levels in the ten subjects at the end of the 3 weeks' administration were between 1.6-2.5 mg/ 100 ml.

There was no significant change in liver volume (Table 2). Antipyrine clearance increased by 90.0 ± 14.1% (mean ± s.e. mean) (P

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Br. J. clin. Pharmac. (1976), 3, 907-913 THE RELATIONSHIP BETWEEN LIVER VOLUME, ANTIPYRINE CLEARANCE AND INDOCYANINE GREEN CLEARANCE BEFORE AND AFTER...
910KB Sizes 0 Downloads 0 Views