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1993;34:582-588.J Nucl Med.

Michela A.L. Edelbroek, Michael Horowitz, Judith M. Wishart and Louis M.A. Akkermans Transit in Normal SubjectsEffects of Erythromycin on Gastric Emptying, Alcohol Absorption and Small Intestinal

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tro intestina l sid e effects. E ry th rom ycin in crease s th e rate

of gastric emptying in normal subjects and in various

form s of gastroparesis (3,8â€”11), s uggesting a potential

role for this drug in the treatment of delayed gastric

em ptying. W hile the increase in gastric em ptying caused

by erythromycin may relate to the stimulation of high

a mplitu de an tral co ntractio ns (6, 1 1â€ ”1 3),h ere is n o info r

mation about the effects of erythromycin on proximal

stom ach m otor function or the intragastric distribution of

a meal. Erythromycin has been shown to modify small

intestinal m otility in anim als (1,2, 14). Inform ation about

the effect of erythrom ycin on sm all intestinal m otor func

tion in hum ans is lim ited and conflicting (6,15).

Alcohol, like many drugs, is absorbed more rapidly

from the small intestine than the stomach, and its rate of

absorption is therefore dependent on the rate of gastric

em ptying (16â€”18). Recent studies suggest that alcohol

unde rgoes s ign if ican t â€œf ir st -pa ssâ€• e tabol ism (19â€”21)by

alcohol dehydrogenase present in the gastric m ucosa (22).

If this is correct, the rate of gastric emptying may theo

retically also influence the total amount of alcohol ab

sorbed, although this has not been evaluated to our

know ledge. Sm all intestinal transit m ay also influence

drug absorption (23).

The aim of this study was to evaluate the effect of

erythrom ycin on gastric em ptying and intragastric distri

bution of a m ixed solid/liquid meal containing ethanol,

alcohol absorption and sm all intestinal transit in norm al

volunteers. T he basic hypothesis w as that erythrom ycin,

by accelerating gastric em ptying, w ould increase the total

amount of alcohol absorbed as well as the rate of alcohol

absorption.

METHODS

Subjects

Paired studies were performed in eight normal male volun

te ers , m ea n a ge 2 3 y r (ra ng e 2 0â €” 29 )n d m ea n b od y w eig ht 7 0 k g

(range 61â€”84),who were all nonsm okers, had no history of

gastrointestinal disease or allergy to erythrom ycin and used no

m edication. A ll drank sm all quantities of alcohol on social oc

casions, but alcohol was not permitted for 24 hr before each

The ef fec tsof ery thromycinon gastr ic empty ingand int ra

gastric distribution of a m ixed solid/liquid m eal, alcohol ab

s orp tio n and sma ll in te stin al tra ns it we re e xam in ed in e ig ht

ma le vo lun tee rs . Each sub ject r eceived, in doub le -b lind r an

domizedorder , e ither erythromyc inas the lactobionate 3

mg . k g1 i.v. o ver 2 0 mm) or salin e immediately before the

consumptionof a radioisotopical lyabeledtest meal ,which

consisted of 330 g m inced beef and 400 m l of orange juice

contain inge thanol 0.5 g . kg@ bodywe igh t)and 10 g lac

tu lo se . E ryth romy cin in cre as ed th e ra te o f to ta l s toma ch

empty in g and p ro xima l s tomach empty in g o f b oth th e s olid

and liqu id componentso f the mea l p < 0.001),bu ts l owed

small in tes ti na lt ransit p < 0.01). Peakb lood a lcoho l con

cen tra ti ons p < 0 .01 ) we re h igher a ft er e ry th romyc in , w ith a

mean in cre as e o f 4 0 . The re was a s ig nific an t in ve rs e re la

tio ns hip b etw ee n p ea k b lo od a lc oh ol c on ce ntra tio ns a nd th e

50 em ptyingt ime for the l iquidcomponentof the mealafter

sa line r = â€”0 .70 , < 0 .05),bu t no ta f te re r ythromyc in r =

â€”0 .5 7, < 0 .1 ). T he to ta l a re a under th e v enou s b lo od

alcoholconcentrat iont ime curve i.e., total absorpt ion)was

greater p < 0.01)aftererythromycin.These resultssuggest

t ha t: f as te r empty ing f rom the prox ima l s tomach contr ibu tes to

mo re r ap id gastr ic empt yi ng induced by e ry th romyc in , e ry th

romycinretardssmall intestinaltransitandthaterythromycin

in crea se s the total am ount o f alcoh ol a bsorbed as w ell as the

ra te o f a lc ohol a bs orp tio n. T he se la tte r e ffe cts a re lik ely to

re fle ct mo re ra pid deliv ery o f a lc ohol to th e sma ll in te stin e

and reducedmetabolismof a lcoholby the gastr icm ucosa.

J NucIMed 993;34:58 â€”588

he widely used antibiotic erythrom ycin has recently

been show n to have profound effects on gastrointestinal

m otor function in anim als (1,2) and hum ans (3â€”6)which

are believed to relate to its properties as an agonist of the

gastrointestinal peptide m otilin (7) and account for gas

Receive dJun.2 4, 1992;revisionacceptedOct.1 4, 1992.

Fo r co rrespondence o r repnn ts contac t :Assoc ia te P rofesso r M. Ho row itz,

Depar tmen t o f Med ic ine , Royal Ade la ide Hospi ta l, No rth Te rrace , Ade la ide ,

South Austra l ia , Austra l ia 5000.

58

The Journalof NuclearMedicineâ€¢ol . 34 â€¢o. 4 â€¢pr il 1993

Effects of Erythrom ycin on G astric Em ptying

Alcohol Absorption and Sm all Intestinal

Transit in Norm al Subjects

M ich ela A L E delb ro ek M ich ael H or ow itz J ud ith M W ish art a nd L ou is M A A kk er ma ns

D ep artm en t o f S urg er y U niv ers ity H osp ita l U tre ch t T he N eth er la nd s a nd D ep ar tm en t o fM ed ic in e R oy al d ela id e

Hospital delaide South ustral ia






g as tric emp ty in g m ea su reme nt. W ritte n in fo rm ed c on se nt w as

ob tained in all case s and th e stud y w as app ro ved b y the E thics

Committ ee o f th e Roya l Adela id e Hosp ita l.

Protocol

E ach v olun teer receiv ed , in ran dom ized o rd er, an intrav e

nous infusion of either erythrom ycin (3 m g . kg â€˜ody w t) as

th e la cto bio na te (A bb ott L ab ora to rie s, S yd ne y, A us tra lia ) o r

n orm al salin e o ve r 2 0 m m, im mediately b efo re eatin g a m ixe d

so lid /liqu id m eal. T he v olum e o f each in fusio n w as 2 0 m l. T he

so lid m eal w as 3 00 g o f coo ked m in ced b eef co ntain in g 2 5â€ ”3 0

MBq o f in -v iv o la be le d @â€œT c-s ulp hu ro ll oi d ch icken l ive r ( 30g)

a nd w as eaten ov er 5 m m. T he calo ric co nten t of th e solid m eal

60 g prote in, 21 g fa t) w as about 600 kca l. The liq uid m eal w as

400 ml in volume and consisted of diluted orange juice (1:1), 0.5

g . kg wt ethanol, 10 g lactulose (Duphalac syrup) and

20â€”25Bq ll3m Indiethylenetr i@ine@ ntaaceticcid DTPA)

an d w as co nsu med ov er 2 m m im med iately after th e solid m eal

18 .The caloric content of the orangejuice total carbohydrate ,

2 1.2 g ; su ga r, 1 6.4 g ; p ro te in , 1 .6 g ; fa t, 0 .2 g )w as 9 6 k ca l a nd fo r

a 70-kg subject an additional 245 kcal w ere contained in the

e th anol. T he c alo ric d en sity o f th e liq uid meal f or a 70- kg s ub je ct

was therefore about 0.75 kcal . m l'. The tem perature of the

liq uid m ea l ra ng ed from 20 t o 2 1Â °Cnd its pH ra ng ed from 3 .9 to

4.1.Ea chtestmea lwasingestedat 10:00a.m.afterthe subject

h ad e ate n n o so lid fo od from 8 .0 0 p .m . a nd d ra nk n o liq uid s from

1 0:00 p .m . th e p rev io us d ay an d ha d av oide d n ona bso rb ab le

ca rb oh yd rates fo r 2 4 hr. A b actericid al m ou th w ash (1 % ch lo

r hexid in e) wa s g iv en immed ia te ly b ef or e inge st io n o f th e meals

to p re vent f ermenta ti on o f c ar bohydr at e by o rophar ynge al b ac

te ri a ( 18 ,24) . B lood s amp le s to meas ure a lc ohol c oncentr atio n

w ere ob tained v ia a cann ula p lace d in a fo rearm v ein . G astric

em pty in g w as m on ito red fo r at lea st 1 80 m m after in gestion o f

th e te st meal, a nd a fte r c omp le tio n o f g as tri c empty ing meas ure

m en ts, each su bject sat in a ch air w hile fu rth er bloo d sam ples

wer e ta ken.

Measurementof Gastr ic Emptying

Deta ils o f th is d ou ble -iso to pe te st h av e b ee n p ub lish ed (2 5â €”

27 . Technetium-99m-sulphur collo id-chicken l iver and H3mIn@

DTPA h av e b ee n d emon stra te d to b e p re cise m ark ers o f d ig est

ible solid and liquid phases, respectively (18). E ach study w as

perform ed w ith the subject sitting w ith his back against the

s cin tilla tio n c am era . D ata w ere c olle cte d in 3 0-se c frame s fo r

th e first 3 0mm , fo llowe d b y 3 -mm frame s fo r th e su bse qu en t 1 50

m m. D ata w ere corrected for subject m ovem ent, radionuclide

d ec ay , C ompto n s ca tte r a nd g amma-ra y a tte nu atio n u sin g p re

v io usly describ ed m etho ds (1 8). T im e 0 w as th e tim e o f liqu id

m ea l in ge stio n. T he to ta l s toma ch re gio n o f in te re st (ROl) w as

d iv id ed in to pro xim al an d d istal reg io ns u sin g an au to mated

c ompu te r p ro gram, w ith th e p ro xim al re gio n c orre sp on din g to

th e fu nd us a nd th e p ro xim al c orp us a nd th e d ista l re gio n re pre

senting the distal corpus and the antrum (25,27). From the

c urv es o f so lid a nd liq uid emp ty in g, e xp re sse d a s a p erc en ta ge

o f th e to ta l m eal rem ain in g w ith in to tal, pro xim al a nd d istal

s tomach ROIs v er su s time , s ev er al p ar ame te rs wer e d eri ve d f or

subsequent s ta ti st ica l analyses .

So li d Meal. Fo r the to ta l s tomach, the parame te rs obta ined

fo r s ta tis tic al a na ly sis we re th e dur atio n o f th e la g pha se b ef or e

a ny fo od e nte re d th e d uo de num, th e 5 0% emp ty in g tim e (T 50 ),

T 50 -lag p ha se an d th e percen tag e rem ain in g at 30 , 6 0, 1 20 an d

1 80 m m after m eal co mpletio n. T he lag p hase w as de term in ed

v is ua lly by t he f rame p re ceding th at i n wh ic h a ctiv ity a ppea re d

in th e p ro xim al sm all in te stin e (2 5,2 6). F or th e p ro xim al s tom

a ch , th e p arame te rs w ere th e 5 0% emp ty in g tim e (p ro x T 50 ) a nd

th e am oun t rem ain in g at 3 0, 6 0, 1 20 a nd 1 80 m m . F or th e d istal

sto mach , the p ercen tag e rem ain in g at 3 0, 6 0, 1 20 an d 1 80 m m

and th e m ax imum c on te nt w as c alc ula te d (2 5,2 7).

Liquid Meal. For the to ta l s tomach, the parameters used were

the duration of the lag phase, the 50% em ptying tim e (T 50),

T 50 -la g a nd th e p erc en ta ge rema in in g a t 1 0, 3 0, 6 0 a nd 1 20 mm .

F or th e p ro xim al sto mach , th e 5 0% em pty in g tim e (p ro x T 50 )

and the am ount of isotope rem aining at 10, 30, 60 and 120 m m

wer e d er iv ed . For th e d is ta l s tomach, th e p er ce nta ge r ema in ing

at 10, 30, 60 and 120 mm and the maximum content were

calcula ted (25,27) .

Measurementof Blood Alcohol Concentrations

In e ac h stu dy , v en ou s b lo od s ample s fo r e th an ol d ete rm in a

tio n w ere ta ke n a t â €” 5, , 1 0, 1 5, 3 0, 4 5, 6 0, 7 5, 9 0, 1 05 , 1 2 0, 1 35 ,

1 50 , 1 65 , 1 80 , 2 10 , 2 40 , 2 70 , 3 00 a nd 3 30 mm a fte r d rin kin g th e

liquid m eal. S am ples of w hole blood w ere stored at 4Â °Cand as

s ay ed w ith in 48 h r f or a lc ohol u si ng gas -liq uid c hromatogr aphy .

T he peak b lo od alco hol con cen tratio n a nd th e areas u nd er th e

v en ou s b lo od a lc oh ol c on ce ntra tio n-tim e c urv e b etw ee n 0 a nd

15 m m, 0 and 30 mm, 0 and 60 mm, o and 330 mm and 90 and 330

m m w ere d eterm ine d. T he b lo od alco ho l c on cen tration in th e

v eno us bloo d sam ple o btain ed 5 m m befo re th e su bject d ran k

the liqu id m eal w as c on sid ere d to b e b lo od eth an ol at tim e 0 .

Measurementof Small IntestinalTransit

Oroce ca l a nd small i nt es ti na l t ra ns it w er e d ete rm in ed by mea

s ureme nt o f b re ath h yd ro ge n c on ce ntra tio ns a fte r in ge stio n o f

th e liq uid m ea l, w hic h c on ta in ed th e n on ab so rb ab le c arb oh y

d rate lactulose (2 8). E nd exp iratory b reath sam ples w ere o h

tam ed im mediately before ingestion of the m eal and subse

q ue ntly a t le as t a t 1 5-mm in te rv als fo r u p to 2 40 mm . Hyd ro ge n

concentration was determ ined by a gas chrom atographic

m etho d (2 8). T he tim e perio d b etw ee n in ge stion of th e liq uid

meal a nd t he f ir st s us ta in ed r is e in b re ath hyd rogen ( an in cr ea se

o f at least 5 pp m o ver b aselin e th at w as m aintain ed fo r at least

30 m m) w as defined as the orocecal transit tim e. T he difference

b etw een o roce cal tran sit an d th e lag p hase fo r the liq uid m eal

w as d efin ed a s th e sm all in te stin al tra nsit tim e (1 8).

Sta tis ti ca l Analy sis

Data w ere a na ly ze d u sin g S tu de nt's t-te st (p aire d d ata ) a nd

lin ea r re gre ss io n a na ly sis sin ce th e d ata c on fo rm ed to a n orm al

d is trib utio n. T he le ve l o f s ig nific an ce , p < 0 .0 5, w as a dju ste d

a ccor ding t o th e number o f v ar ia bl es te ste d (Bonf er roni c or re c

tio n). Mea n v alu es Â±s .c .m . a re re po rte d in th e te xt.

RESULTS

All subjects tolerated the study well. During the infu

sion of erythrom ycin, two subjects reported m ild nausea

and three subjects experienced muscle cramps in the

upper arm above the site of adm inistration. These effects

were minor and transient. No untoward effects were re

ported during the infusion of saline.

583

ry th romyc in , A lcoho l and Gastr oi nt es ti na l Func ti on Edelbr oek a t a l.






P roxima l Stoma ch. The prox T50 77 Â±11 mm ver sus

109 Â±12 mm, p < 0.05) and the amount remaining at 120

and 180 mm were less (p < 0.03) after erythromycin when

compared to the placebo (Fig. ib).

Dista l Stomach. The amount of the mea l in the dista l

stomach at 120 and 180 mm was less af ter erythromycin

(p < 0.03) (Fig. ic). During the 3-hr period, there was no

dif ference in the maximum content of the distal stomach

(38 Â±1 versus 42 Â±2 , ns) or the time of maxi

mum content (94 Â±17 mm versus 103 Â±15 mm, ns).

Liq uid Mea l

To ta l Stoma ch . In a ll su bje cts th e emp tyin g c ur ve fo r

the liquid meal was nonl inear and usually approximated a

mono-exponential pattern after a short lag phase (Fig.

2a) . Total gastric emptying was faster af ter erythromycin

when compared to sal ine, w ith a decrease in the lag phase

(2 Â±0.3 mm versus 5 Â±0.6 mm, p = 0.001), the T50

(34 Â±4 mm versus 76 Â±9 mm, p < 0.001) and the T50-lag

(32 Â ±4 mm versus 71 Â ±8 mm, p < 0.001).

P roxima l Stomach. The prox T50 6 Â±2 mm ver sus 20

Â±3 mm, p < 0 .0 01 ) and t he amount remain in ga t 1 0, 3 0 ,

60 and 120 mm were less (p < 0.05) after erythromycin

when compared to the placebo (Fig. 2b).

Dista l Stoma ch. The a mount of liquid mea l in the dista l

stomach at 30, 60 and 120 mm was less (p < 0.02) after

erythromycin (Fig. 2c). There was no significant differ

ence in the maximum content of the distal stomach be

tween the two tests (41 Â±2 versus 39 Â±2 , ns) .

Rateo f Calor icGas tricEmp tying

The rate at which calories entered the duodenum was

faster af ter erythromycin than sal ine in the postprandial

period between 0 and 60 mm (4.1 Â± 0.3 kcal . min

versus 2.7 Â ±0.2 kcal . min@, p = 0.001) and 60 and 120

mm (3.0 Â±0.3 kcal .m in versus 2.4 Â±0.3 kcal .m in ,

p = 0.029), but not between 120 and 180 mm (3.1 Â ±0.3

kcal .m in versus 3.0 Â±0.3 kcal â€˜in , ns).

B l o o dA lc o h o lC o n c e n t ra t io n s

The blood alcohol concentration was zero in all sub

jects at 330 mm. The areas under the venous blood alco

hol concentration-time curves between 0 and 15 mm, o

and 30 mm, 0 and 60 mm, o and 330 mm and the peak

blood alcohol concentration were all higher (p < 0.01)

after erythromycin compared to saline (Table 1, Fig. 3).

The mean peak blood alcohol concentration was about

40 higher after erythromycin and total alcohol absorp

tion (area under curve between 0 and 330 mm) was about

14 higher a fter e ry th romycin when compared to sa line .

There was no signi fi cant di fference between the two tests

in the area under the blood alcohol concentration-time

curve between 90 and 330 mm (T able 1).

R e la tio n s h ip B e t w e e n G a s t ric E m p ty in g a n d A lc o h o l

A b s o r p t io n

There was an inverse relationship between peak blood

alcohol concentration and the total stomach T50 for the

SOLID MEAL

10 0

80

I

60

40

20

Time (mln)

10 0

b)ProxImal stomach

â€”@ s a l in e

â €” 0â €” - esythromycln

80

@60

40

20

60 90 120

TIme mln)

10 0

)D Is ta l s tomach

80

â€”@ s a l in e

â €” â €” e ry th ro m y in

g

60

40

20

0 30 60 90 120

150 iÃ¨o

TIme mln)

FiGURE1. Gas tricmp ty ingndintrag as tricis tribut ionf

t he so lid mea la f te r sa line and erythromyc in . *p < 0.05 ad jus ted

fo r th e number o f v aria ble s te ste d.) Da ta a re mean valu es Â±

s.e.m.

Gastric Empty in g

So li d Mea l

Tota l Stoma ch. In a ll subjects solid emptying wa s

slower than liquid emptying af ter both sal ine and eryth

romycin and was characterized by an initial lag phase

fol lowed by an empty ing phase that approximated a l inear

pattern (Fig. la). Erythromycin resulted in more rapid

emptying, with reductions in the lag phase (35 Â±7 mm

versus 63 Â±8 mm, p = 0.002), the T50 (166 Â±13 mm

versus 220 Â±15 mm, p = 0.001) and the T50-lag (131 Â±10

mm versus 157 Â ±13 mm, p < 0.05).

5 8 4

The Jou rna l o f Nuclea r Medi ci ne â€¢o l. 34 â€¢o . 4 â€¢p ril 1993






100

Par ame t e rSa l i n eE ry th r omyc inpPeak

a l coho l (mg/ i00 ml )55

Â±47 7

Â± 2Area

unde r c u r v e0 â€” imm338

Â±45585

Â±60 .002(mg/ i

00I/mm)Area

unde r c u r v e0 â€”30m1057

Â±80 16 10

Â±20 .001(mg/ i

0 0I /mm)Area

un de rcu rve0â €”60m 25 28

Â±1 2 3 33 6 9 Â±10 .001(mg/ i

0 0I/mm)Area

unde r c u r v e0 â€”330m6658

Â±2697614

Â±460 .008(mg/100

mI/mm)Area

unde r c u r v e90â€”330m2908

Â±2 4 3 30 3 3 Â±12n s (mg / i

0 0I/mm)*Data

a r emeanva lu esÂ± .e .m .

30 60

90 120 150

T ime (m ln )

1 80

B lood A lcoho l Conc en tr a tio n s *

IQUIDMEAL

(a)Tota l s tomach

sailne

â€”aâ€”â€” erythromycin

80

C

0

60

40

20

100

( b )P r o x Ima l s t omach

â€” â€” saline

â€ ” 0â€ ” - er yt hr om ycl n

80

J o

O ro c e c a la n d S m a llIn t e s tin a lTrans i t

Erythromyci n prol onged both orocecal 101 Â ±13 mm

v ersus 73 Â ±9 mm, p < 0.01 and smal l i ntesti nal 99 Â ±13

mm versus 68 Â ±9 mm, p < 0.01 transi t Fig. 5 .

DISCUSSION

Effe ctof Erythrom ycinon G a s tricEm ptying ,

Intrag as tricDis tribu tionan d S m allInte s tina lTrans i t

Our resul ts show that ery thromy ci n i n an i ntrav enous

dose of 3 mg . k g â€ncreases the rate of gastri c empty ing

of sol id and caloric l iquid meal components in normal

subjects and that this is associated wi th changes in the lag

phase, the em pty ing phase and prox im al stom ach em pty

i ng of a meal . T hi s l atter observ ati on suggests that ery th

rom yci n i nf luences prox im al stom ach m otor f uncti on and

i s consi stent w ith a recent report of pati ents w ith progres

sive systemic sclerosis in which an increase in the num

ber of f undi c contracti ons was observ ed af ter ery throm y

cm 29 . Simi lar doses of erythromycin have been

reported to i ncrease the number and ampl itude of antral

contractions in both fasting and postprandial states

(6 ,1 2 ,1 3 ) a n d to d e c re a s e th e n u m b e r o f p re s s u r e w a v e s

i solated to the pylorus 12 in normal subjects. The in

crease i n antral contracti ons caused by erythromyci n i n

dogs is associated w ith impaired tri turation of a sol id

meal , so that a greater proporti on of larger parti cl es > 0.5

mm enter the smal l i ntesti ne 30 . W hi le our resul ts i n

dicate that faster emptying f rom the proximal stomach

contributes to more rapid gastric emptyi ng induced by

ery thromyci n, ef fects on di stal stomach moti li ty are al so

l i kel y to be important 2, 1 2, 1 3 . D i stal stom ach em pty ing

i s di f fi cul t to evaluate w i th scinti gr aphi c methods because

of the v ari abl e i nput f rom the prox imal stomach.

U rbai n et al . 3 and Janssens et al . 8 r eported that

ery thromyci n abol ished the characteri sti c di ff erence i n

gastri c empty ing of sol ids and l iqui ds i n normal subj ects

a nd p a tie n ts with d ia be tic g as tro pa re s is . W e fo un d th a t

gastri c em pty ing of the sol i d m eal was sti ll substanti al ly

60

40

20

TIme(mln)

( C )D Is t a l s t oma c h

â €” â€ ” sa lin e

â€”0â€¢â€”- erythromycin

100

80

0

J

60

40

20

0

30 6 0 9 0 1201 50180

TIme(mln)

FIGURE2. Gas tricmp ty ingndintrag as tricis tribut ionf

the liqu idme a la fters a lineand e ryth rom ycin .*p < 0 .05ad jus ted

fo r th e n umbe ro f v a ria b l e ste s te d . )D a t a a r e me an v a lu e s Â±

s . e .m .

l iqui d meal af ter sal ine r = 0.70, p < 0.05 , but not af ter

erythromyci n r = â€” 0.57,0.05 < p < 0.1, ns Fi g. 4 . T he

ar eas under the venous blood al cohol concent rat ion- time

curve betw een 0 and 30 mm and 0 and 60 mm correlated

w ith the amount of l iqui d empti ed f rom the total stomach

at 30 mm and 60 mm af ter sal ine r = 0.69, p < 0.05 and

r = 0.68, p < 0.05, respecti vel y but not af ter ery throm y

cm r = 0.05, ns and r = 0.11, ns, respectively .

5 8 5

ry th romy c in , Alc o h o l a n d G a s t ro in te s t in a l F u n c tio n â € ¢d e lb ro e k e t a l.

TABLE1






360

60 120 180 240 300

a

80

p = 0 003

150

â € ” 1 2 0

U)

C

U)

I-

: g o

U)

. â€ ˜E '

U)

E

U

U,

0 __________

sal in e ery th rom yc in

860

@ 40

j20

0

â€” saline

â € ”a â € ” e ry th ro m yc in

Po s t c l b a lmInu t e s

FIGURE 3 B loo dalcoho lcon centra t ionsf te r sa l ineand

e r yth r omyc in .*p < 0 . 0 5 a d ju s t e dfo r th e n umbe ro f v a r ia b le s

te s te d .) D a ta a re m e a n v a lu e s Â±s . e .m .

slower than that of the liquid meal after erythromycin

injection. The explanation for this apparent discrepancy

may relate to technical f actors or the composition of the

test meal . The f requent data acquisi tion used in our study

enabled accurate quantification of patterns of gastric

emptying. A short lag phase, or the early phase of liquid

gastric emptying, may not be able to be evaluated accu

rately by acquisition rates of 10â€”15mm (3, 8). The test

meal used by U rbain et al. (3, 8) was smaller in volume,

incorporated a noncaloric (water) rather than a caloric

liquid component and solid components (eggs, bread)

which may have been easier to triturate than the minced

beef used in our study. I t is nevertheless clear that eryth

romycin in low dosages (â€”3mg . kg â€.v.) , unlike other

gastrokinetic drugs (31), signi ficantly increases the rate of

20

FIGURE 4 Relat ion sh ipetw eenpeakb loo dalcoh olevels

a nd th e 5 0 e m ptyin g tim e o f th e liq uid te s t m e a l a fte r s a lin e

a n d e r yth romy c in .

FIGUR E5 Sm allnt est in alran si tf tersal in endery th ro m y

cm .Sm a llinte s t ina lran s itwa s de term ine dbys ub tra ct inghe la g

p ha s e o f th e liq uid c om p on e nt o f th e m e a l fro m th e o ro ce c a l

tra n s it t im e m e a s u r e d b y b re a t h h y d ro g e n a n a ly s is .

gastric emptying in normal subjects to above â€œphysiolog

icalâ€• level s ( 18,32,33) , whi ch is consistent w ith the ob

servation that erythromycin is able to overri de the small

intestinal feedback signals that regulate gastric emptying

1 2, 3 1, 3 2 . Our o bse rva tio n that the ra te o f ca lo ric dcliv

cry to the small intestine was not enhanced by erythro

mycin between 120â€”180mm likely reflects the lower

plasma concentrations of erythromycin at this time and is

consistent with Sarna et al. (6) who reported that the

increase in antral contractions af ter erythromycin ( 500

mg i.v.) is most marked in the first 30 mm after drug

administration and is related to plasma concentrations of

erythromycin.

Intravenous administration of erythromycin has been

shown to imprive delayed gastric emptying in patients

w ith gastroparesis secondary to diabetes melli tus ( 3,8) ,

vagotomy (34) , progressive systemic sclerosis (10) arid

primary anorexia nervosa (11) and i ts action appears to be

more potent when compared to other gastrok inetic drugs,

such as metoclopramide and cisapride. Erythromycin haS

also been used to facilitate the transpyloric passage of

enteric feeding tubes (35) and manometric catheters (36).

Enthusiasm for the potential rol e of erythromycin in the

treatment of gastroparesis should, however, be tempered

with the real izations that: oral administration may be less

ef fective [al though i t has been shown to increase gastric

emptying substantial ly (3,8) ], the effects of erythromycin

on gastrointestinal symptoms associated with gastropare

sis have not been evaluated and that the long-term effi

cacy of erythromycin in improving gastric emptying has

not been clearly establi shed (9) . I n particular, it has been

suggested that i ts gastrok inetic action wil l diminish with

100

E

8

E

0

0

U

2

@

a .

a

â€ ¢sa line

r= O 7 0; p@ O O 5

80

a a

U

a

U

an

a erythromycln

r= O 5 7; p @O 1

60

U

U

40

2 4 6 8 2

LIq u Id 5 0 e m p t yIn g tIm e (m ln )

586

T he J o u rn a l o f N uc le a r M e dic in e â € ¢o l. 3 4 â € ¢o . 4 â € ¢p ril 1 9 9 3






time due to down-regulation of motilin receptors (37).

There is considerable interest in derivatives of erythro

m ycin that are m otilin agonists devoid of antibiotic activ

ity (3 8).

It is clear that the effects of erythromycin on human

gastric and intestinal m otility are dose-dependent (6). F or

exam ple, in the sm all intestine, low doses (1â€”3m g . k g@ )

of erythromycin induce phase-3 activity in normal sub

je cts (5 ) a nd in p atie nts w ith in te stin al p se ud o-o bstru ctio n

39), while higher doses 7 mg . kg ) prolong the cycle

length of the interdigestive m igratory m otor com plex and

in duce g ia nt retro grad e co ntraction s (5 ). O ur o bserv ation

that erythrom ycin retards sm all intestinal transit is con

sistent with the findings of Sarna et al. (6) who reported

that erythromycin in an intravenous dose of 500 mg re

duced the frequency and duration of sm all intestinal con

tractions in the fed state. This is in contrast with Lehtola

et al. (15) who reported that single oral doses of erythro

m ycin stearate (1000 m g) or erythrom ycin acistrate (800

mg) shortened orocecal transit in healthy subjects. The

lactulose load in their study was greater (26 g) and was

consumed w ithout a m eal. Because gastric em ptying w as

not quantified, it is possible that the observed decrease in

orocecal transit sim ply reflected enhanced gastric em pty

ing of lactulose rather than more rapid small intestinal

transit. It is also possible that the accelerated rate of

gastric emptying may have contributed to slower small

intestinal transit. F or exam ple, the presence of nutrients

in the ileum delays sm all intestinal transit (40). H ow ever,

the m ost likely explanation for this discrepancy relates to

a difference in dosage of erythrom ycin in our study (2,6).

In particular, Lehtola et al. (15) used an oral dose of

erythromycin. An indirect effect of erythromycin on

sm all intestinal transit related to alterations in colonic

bacterial flora can be excluded in both studies on the

basis that only a single dose of erythromycin was used at

submaximal antim icrobial dosages (41). The measure

ment of small intestinal transit by hydrogen breath anal

ysis does not allow us to speculate whether the delay in

sm all intestinal transit induced by erythrom ycin reflects

slowing of transit in the jejunum or ileum (or both).

E ffect of E rythrom ycin on A lcohol Absorption

O ur study dem onstrates that erythrom ycin in an intra

venous dose of 3 mg . kg â€ncreases the total amount of

alcohol absorbed and the rate of alcohol absorption. The

close relationship between peak alcohol levels and the

rate of liquid em ptying after intravenous saline is consis

tent w ith previous observations, indicating that the m ajor

factor influencing the rate of alcohol absorption is the rate

of delivery to the sm all intestine from which it is rapidly

absorbed (16â€”18).For exam ple, peak blood alcohol con

centrations are increased by metoclopramide (42) and

after a gastric drainage procedure (16, 4 3). Factors w hich

slow gastric emptying, such as ingestion of a solid meal

1 8), anticholiner gic drugs 42), cigarette smoking 44)

and infusion of fat into the sm all intestine (45), decrease

peak blood alcohol levels. Recent studies indicate that

alcohol, w hen adm inistered inlow doses (0.15 m g . k g'),

is su bjected to sig nifican t first-p ass m etab olism (1 9â€ ”2 1),

probably by alcohol dehydrogenase present in the gastric

m ucosa (22). The results of our study support the hypoth

esis that first-pass m etabolism of alcohol by the gastric

mucosa is clinically important. Erythromycin is not

know n to affe ct alc ohol m etabolism directly and the in

creased total alcohol absorption of about 14% is likely to

be related to more rapid gastric emptying and hence re

duced exposure of alcohol to the gastric m ucosa. Slower

small intestinal transit may also favor increased drug

absorption (23), but since there was no difference in al

cohol absorption after the first 90 mm, this is unlikely to

be a m ajor factor.

O ur observations potentially have both social and m cd

icolegal implications for patients who are prescribed

erythromycin. It is the task of the treating physician to

point out the possible effects of erythrom ycin (and other

drugs that influence gastric em ptying) on alcohol absorp

tion, although it is possible that oral erythromycin will

have less effect (8, 9). Our results suggest that the effects

of erythromycin on blood alcohol concentrations are

likely to be greater in those patients who have reduced

lev els o f g astric alco hol d eh ydro gen ase, in clu din g w om en

2 1), pati ents after gastr ectomy 20) and patients taking

c im etid in e (4 6).

ACKNOWLEDGMENTS

T he a uth ors th an k D r. B . C ha tte rto n, D ep artm en t o f N uc le ar

Medi cin e, Royal Adel aid e Hosp ita l f or p ermit tin g th e s tudie s to

b e p erfo rm ed in h is d ep artm en t a nd D r. C . H ah n o f th e D iv is io n

o f C lin ic al C hemistry , In stitu te o f Med ic al a nd V ete rin ary S ci

e nc e fo r p erfo rm an ce o f th e b lo od a lc oh ol m ea su reme nts . T his

study w as supported by grants from the N ational H ealth and

M ed ic al R ese arc h C ou ncil o f A ustralia an d N W O M ed ical R e

s ea rc h, T he Ne th er la nd s ( gra nt 900 -522 -082 ).

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ay j nucl med 1993 edelbroek 582 8

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