398

RANITIDINE AND LIVER BLOOD FLOW

SIR,-Dr Feeley and Elizabeth Guy’s letter (Jan. 16, p. 169),reporting a reduction in indocyanine-green (ICG) clearance afteroral ranitidine, raises a number of points. To assume that thischange in clearance is due to a fall in liver blood flow may beerroneous since hepatic extraction of the dye was not measured.

I

For substances with high hepatic extraction, such as ICG, a fall inliver blood flow by the amount observed (18%) would be

accompanied by an increase in hepatic extraction of about 4%, sothat the true change in liver blood flow would be greater than themeasured fall in systemic clearance.

It seems that ICG clearance was measured before and 60 min after150 mg ranitidine. In support of this Feeley and Guy cite twopapers,3 purporting to show the reproducibility of repeatedestimates of liver blood flow on the same day, but in neitherreference are such data to be found. In our experience, even withsmaller doses of ICG (0’ 25 mg/kg), clearance of the second dose isimpaired by at least 15%, if this is administered within 90 min.These two errors, which affect estimated liver blood flow in

opposite directions, may not cancel each other out and makeinterpretation of the Dundee workers’ data difficult.Whilst we agree that a fall in liver blood flow will reduce the

elimination of drugs subject to high hepatic extraction, this appliesonly if the drug is administered parenterally. After oraladministration of propranolol and similar drugs, the reducedsystemic clearance will be exactly balanced by increased hepaticfirst-pass extraction,4 leading indeed to lower peak blood

concentrations, although the drug’s half-life will be prolonged.Further, since the half-life of ranitidine is short, between 2 and 3 h,5its effect on liver blood flow may be only transient. Under thesecircumstances, those drugs with longer half-lives and subject tohigh hepatic extraction, when taken by mouth at the same time asranitidine, will have their bioavailability actually reduced.

Gastrointestinal Laboratory,Rayne Institute,St Thomas’ Hospital,London SE1

S. L. GRAINGER

J. H. MARIGOLDP. W. N. KEELING

BLEEDING TIMES AND FISH DIETS

SIR,-Dr Thorngren and Dr Gustafson (Nov. 28, p. 1109) do notgive values for cutaneous bleeding time but they can be estimatedfrom their fig. 1. For the ’Simplate II’ device the mean pretreatmentcutaneous bleeding time seems to be 9-3 3 min, and extrapolationfrom the SEM bar suggests that the bleeding-time was up to 12 8min in individuals before the fish diet. This is in great contrast towhat is found elsewhere. Others, using the same technique, findmean cutaneous bleeding times of 4 1,6 4 - 75, and, in healthyyoung people studied by us, 4’76 min.8 The range in these threeseries is 2-3-8 min. Results so different from those hitherto

reported deserve comment. Technical problems could be the reasonfor the discrepancies.Department of Clinical Chemistry,Section of Blood Coagulation,Aalborg Hospital,9100 Aalborg, Denmark JØRN DYERBERG

1. Lebrec D, Goldfarb G, Benhamou JP. Reduction of liver blood flow by cimetidine. NEngl J Med 1981; 305: 100.

2. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The use of indocyaninegreen in the measurement of hepatic blood flow and as a test of hepatic function. ClinSci 1961; 21: 43-57.

3. Leevy CM, Mendenhall CL, Lesko W, Howard MM. Estimation of hepatic blood flowwith indocyanine green. J Clin Invest 1962; 41: 1169-79.

4. McLean AJ, McNamara PJ, duSouich P, Gibaldi M, Lalka D. Food, splanchnic bloodflow, and bioavailability of drugs subject to first-pass metabolism. Chn PharmacolTher 1978; 24: 5-10.

5. Bogues K, Dixon DT, Fowler P, Jenner WN, Maconochie J, Martin LE, WilloughbyBA. Pharmacokmetics and bioavailability of ranitidine in humans. Br J Pharmacol1981; 73: 275P.

6. Babson SR, Babson AL Development and evaluation of a disposable device forperforming simultaneous duplicate bleeding time determinations. Am J Clin Pathol1978; 70: 406-08

7 Kumar R, Ansell JE, Canoso RT, Deykm D Clinical trial of a new bleeding timedevice Am J Clin Pathol 1978: 70: 642-45

8. Stoffersen E. Bleeding time determination ad modum Ivy. Ugeskr Laeg (in press)

THE BLOOD-BRAIN BARRIER IN ENCEPHALOPATHY

SIR,-Last August we expressed doubts about the "unifiedtheory of portal-systemic encephalopathy" proposed by James,Fischer, and colleagues.2 Mr James and Professor Fischer haveresponded with a spirited defence of their ideas (Dec. 19/26, p. 1420),but we are not reassured.One striking change during portal-systemic shunting is a very

large rise in brain glutamine content to 20-25 JAmollg (normal 6).The "unified theory" proposes that glutamine facilitates the

transport of neutral aminoacids at the blood-brain barrier by anexchange mechanism. We pointed out that glutamine was not asuitable candidate for this purpose kinetically since it is very weaklytransported by the neutral aminoacid carrier. James and Fischerargue that the major issue is the relation between the concentrationof glutamine on the antiluminal surface and the Km of glutamine fortransport. They point out that the Km of glutamine, in the absenceof competitors, is 8 - 5 mmol/1. Thus, an increase of brain glutaminefrom 6 to 20 mol/g could substantially affect the transport carrier.This argument holds only for in vitro systems. Nine other neutralaminoacids compete with glutamine in vivo. 3 Their affinities for thetransport carrier and their concentrations make them highlyeffective competitors. As a result glutamine will not have muchaccess to the carrier. The apparent Km of glutamine in vivo is muchgreater than 8 - 5 mmol/l. Taking into account likely aminoacidconcentrations in plasma and brain, it could be as high as 46 mmol/l.James and Fischer acknowledge that their "theory" does not

explain decreased basic aminoacid and monocarboxylic acid

transport. We agree that failure to account for these changes doesnot necessarily disprove this theory for neutral aminoacid transportand apologise if we implied that it should. However, we suggest thatJames and Fischer ought to consider a more conservative title than"unified theory".We noted that the theory cannot explain why the transport of

three different neutral aminoacids was increased to different

degrees. James and Fischer point out that, using different

techniques, they4 and Zanchin et al. found that brain uptakeindices of various neutral aminoacids were increased to nearly thesame degree. However, in Zanchin’s study, tryptophan transportincreased by 168% compared with increases of only 7007o for

tyrosine, phenylalanine, and others.Perhaps the most difficult experiments to reconcile with the

theory are those of Cardelli-Cangiano et al. Cerebral microvesselsfrom rats with portacaval shunts showed changes qualitativelysimilar to those found in vivo. However, their glutamine contentwas only 0 - 6 jumol/g, compared with whole brain glutamine contentin shunted rats (20-25 JArnol/g). Therefore, it is very unlikely thatglutamine could be a significant factor in stimulatimg the transportsystem, at least under these circumstances.In summary, the "unified theory of portal-systemic encephalo-

pathy" explains far less than the title suggests, and even whenattention is limited to neutral aminoacid transport the theory seemsinvalid.

Departments of Physiologyand Anesthesia,

M.S. Hershey Medical Centerof Pennsylvania State University,

Hershey, Pennsylvania 17033, U.S.A.

RICHARD A. HAWKINSANKE M. MANS

JULIEN F. BIEBUYCK

1. Hawkins RA, Mans AM, Biebuyck JF. Blood-brain barrier during portal-systemicencephalopathy. Lancet 1981; ii: 302.

2. James JH, Jeppsson B, Ziparo V, Fischer JE. Hyperammonaemia, plasma ammo acidimbalance and blood-brain amino acid transport: a unified theory of portal-systemicencephalopathy. Lancet 1979; ii: 772-75.

3. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrieramino acid carriers. Am J Physiol 1976; 230: 94-98.

4. James JH, Escourrou J, Fischer JE. Blood-brain neutral ammo acid transport activity isincreased after portacaval anastomosis. Science 1978; 200: 1385-97.

5. Zanchm G, Rigotti P, Dussini N, Vassanelli P, Battistin L. Cerebral amono acid levelsand uptake in rats after portacaval anastomosis II: Regional studies m vivo JNeurosci Res 1979; 4: 301-10.

6. Cardelli-Cangiano P, Cangiano C, James JH, Jeppsson B, Brenner W, Fischer JEUptake of amino acids by brain microvessels isolated from rats after portacavalanastomosis. J Neurochem 1981; 36: 627-32.