Passage of paracetamol into breast milk and its subsequent metabolism by theneonate
L. J.NOTARIANNI1,H. G.OLDHAM2& P.N.BENNETT'
'SchoolofPharmacy andPharmacology,UniversityofBath, andClinicalPharmacology Unit, RoyalUnited Hospital, Bath,2DMPK,Smith Kline and French ResearchLtd,TheFrythe, Welwyn,Hertfordshire
1 Paracetamol was administered to nursingmothers. Thedrug passed rapidly intomilk and themilk:plasma concentration ratiowasapproximately unity.
2 The estimated maximum dose to the neonate was 1.85% of the weight-adjusted maternaloraldose ofparacetamol 1.0g. Recoveryofparacetamolwasgreaterfromthe breastfromwhichsamplesweretakenfrequentlythanfrom the breast whichwassampled only once.
3 Paracetamol, its glucuronide, sulphate, cysteine and mercapturate conjugates were found inthe urine ofthe neonatesalthough onlytheparentdrugwasdetected inbreast milk.
4 The neonatesexcretedsignificantlygreaterproportions ofunchanged paracetamol (P
<0.01) and significantlylesserproportionsofparacetamol sulphate (P<0.001) than did healthy volunteers aged 11-80yearswhoreceivedatherapeuticdose ofparacetamol.
5 Thefindingsarecompatible withadeficiencyofsulphate conjugation bythe neonate.
Keywords paracetamol neonate metabolism breast milk biotransformation
Paracetamol is widely used as a post-partum analgesic innursing mothers (Passmore etal., 1984; Matheson, 1985).Itis believedtopresent no risk to the suckling infant since less than 0.25% ofamaternalsingledoseis estimatedto reach the child(Berlinetal., 1980;Bitzenetal., 1981). As many drug metabolic reactions are
deficientinthenewborn(Rane&Wilson,1983), ingestion of seemingly small quantities of drug may assumeimportance. Levyetal. (1975)and Miller et al. (1976) found that neonates had limited capacityto conjugate paracetamolwith glucuronic acid but that sulphate conjugation waswell developed.
(a) Four volunteer nursing mothers (a,b,c,d)
aged26-37yearsand2-8 months post-partum, breast-fed their babies in theClinical Pharma- cology Unit, Royal United Hospital,Bath. Each mother then received paracetamol 1.0 g as a single dosebymouth. Blood and milk samples weretakenconcurrentlyevery30 min for 3.0-3.5 hthereafter,the milkbeing taken from the same breast each time by means of an electrically- driven breast pump which extracted all the avail- able milk. Nosamples were taken from the other breast untiltheendofthestudy when all avail- able milkwasextracted from it also.
(b) Paired milk and blood samples were obtained from ninenursing mothers aged 20-38 years,2-10daysafterdelivery;each hadreceived paracetamol (1.0-2.0 g) in the preceding 12 h for post-partumpain.
(c)Six infants (2-6days old) of five mothers aged 28-30years(E,F,G,H,I) (onewith twins) who took paracetamol for post-partum pain, werestudied. The infants received paracetamol 63
via the breastmilk and neither the doseadmini- steredtothemothernorthe timing of the feed after dosingwasinfluenced by the requirements of the study in any way.The mothers received paracetamol(1.0-2.0 g) 2.0-4.0 h before breast feeding; immediately after each infant had suckled, a 'Coloplast' baby urine collector was
appliedtoit and urinewascollected for 1.0-3.5 h (Table 1).
(d) Forty-nine healthy male and female volun- teersaged 11-80years,comprising hospital and universitystaff and fit elderly patients contacted from general practitioner lists, received para-
cetamol 0.5 g or 1.0 g as a single oral dose.
Paracetamol and metabolites were assayed in urinecollectedoverthenext8 h.
All the studies were approved by the ethics committee of the Bath Health District.
The pH and volume of each milk samplewere
measuredimmediatelyuponcollection and milk, plasma and urine sampleswerestoredat-20° C priortoanalysis.
Paracetamol (P) and its glucuronide (PG), sulphate (PS), cysteine (PC), and mercapturic acid (PM) metabolites were assayed by high performance liquid chromatography using a
modification of the method of Adriaenssens &
Prescott(1978). The values foreach metabolite
wereconvertedtotheequivalent weight ofpara-
cetamol fromwhich itwasderivedbycorrection for molecular weight. All values were then expressedas apercentageof thetotalrecovery.
Standard metabolites were the gift of Dr R.
Andrews, Sterling Winthrop R & D, Newcastle.
0.2-30mg1-1(paracetamol), and 0.5-50mg1P1 (metabolites). The coefficients of variation at 0.5 mg 1-1 were 6% (paracetamol) and 8%
The areasunder the concentration-time curves werecalculated by the trapezoidal ruletothe last datumpoint.
(a) Figure 1 shows milk and plasmaconcen-
tration-timeprofilesinthevolunteers whotook paracetamol 1.0gby mouth (Subjects, a). Fol- lowing its ingestion by the mother, paracetamol rapidlyentered milk and the milk concentration exceededthat inplasma in each volunteer. The
mean area(±s.e.mean) under the milkconcen-
tration-timecurve was21.10±4.63mg1-1h and that for plasmawas13.08 ±2.75mgI-1 h.
Themeanmilk:plasmaconcentration ratio for 21paired samples in the four volunteerswas1.24
+ 0.12; this value refersto maturemilk. Seven milk samples (at leastone from each mother)
wereassayed for metabolites of paracetamol but
none was detected, the limit of detectability being< 100ngml-'.
Figure 2 shows that both the concentration of paracetamol in milk and the milk volumeswere
higher in the breast thatwasexpressedevery30 min for 3.0-3.5 h, compared with the breast that
wassampled onlyonceatthe end ofthe collection period.
Table 1 Recovery ofparacetamol and its metabolites in the urineof breast-fedneonates
Paracetamol Dose-feed Urine andmetabolites Dose interval collection in urineof Mother (g) (h) time(h) neonate(,ug)
E 1 3.5 3.0 85.2
F 1 3.2 3.5 59.8
G(1)* 1 2.0 2.5 27.6
G(2)* 1 2.0 1.0 486.6
H 2 4.0 3.0 822.2
I 2 4.0 3.5 921.9
Urinecollectionscommencedimmediately after feeding had beencompleted. Paracetamol recovered includes all metabo- lites correctedfor molecular weight. *Indicatestwin babies;
the infantG(2) produced10.5mlurinecompared to0.6 ml by his sister.
1 2 3
1 2 3
1 2 3
1 2 3
Figure1 Milk(L)andplasma (0)concentrations ofparacetamolinfour volunteers afteradministration ofparacetamol1.0gbymouth.
Figure2 Paracetamolconcentr frombreastsemptiedat30minit single expressionat3.0-3.5 h(o and d.Thefiguresin bracketsgiv
(b) The mean milk:plasn
27.6-921.9,ug (mean±s.e.mean,400.6±164.5 ,ug); the large variation reflects differences in urinevolume,collectiontime,dosereceived and the intervalfrom dosetofeed. Therecoveryof paracetamoland its metabolites in theseinfants
(37) ispresentedinTable2. Allthe babiesexcreted 0(95) paracetamol, PGandPS,butPCorPMwerenot 0(9*5) found ineveryurine. Themajormetabolitewas
PG,followed indecreasing proportion bypara-
0(16) cetamol,PC +PM,and PS. Sincenometabolites weredetectedinmilk, itwasassumed thatthese productsweresynthesised by theneonates.
c d (d) A summary of thepercentages ofpara- cetamol and its metabolites recovered fromthe ntervals(m)andafter urine of healthy volunteers (Subjects, d) also )in volunteersa,b,c appears in Table 2. The neonates excreted a
vethe volume of milk significantly greaterproportionofparacetamol
(P< 0.01)andasignificantlylesserproportion ofPS(P<0.001)thandid thevolunteers. Full details of the findings inthe volunteers willbe
na ratio for para- reportedelsewhere.
cetamol in the samples obtained from nine mothers who took thedrugfortherapeuticpur- poses (Subjects, b)was0.95 ± 0.16; this value referstocolostrum and transitional milk andwas notsignificantly different from that obtained in maturemilk(Subjects, a).
(c)Table 1 shows that the totalamountofpara-
cetamol and its metabolites excreted by the neonatesintheir urine(Subjects, c) rangedfrom
Thefactors thatgoverndrugpassageinto breast milk arelikely tobe those that influence drug transfer elsewhere in the body. The physical characteristics ofparacetamol suggest that the drugshould diffusereadilyinto milkfor it hasa
a) cg I X 10 a.
Table 2 Percentage recovery ofparacetamolandits metabolitesin the urineof neonates and ofhealthyvolun- teers aged 11-80 years
P PG PS PC+PM
Neonates (n = 6)
Mean 24.9 54.1 9.9 11.1
s.e. mean 6.6 6.0 1.9 3.2
Range 9.5-46.9 32.8-71.3 5.0-18.3 0-20.5 Healthy volunteers
(n = 49)
Mean 5.2 52.1 35.1 7.4
s.e.mean 0.7 1.4 1.5 0.5
Healthyvolunteerstookparacetamol 0.5 g(n =2)or 1 g (n= 47) by mouth; urinewascollected for8 h.Neonates received paracetamolindirectly viathe breast milk.
pKa of9.5, is largelyunionisedatphysiological pH andbindingtoplasmaproteins islow. Our data show that paracetamol passesrapidly into milk andthemilk:plasma concentrationratio is approximately unity. Other workershave made similarfindings(Berlinetal.,1980; Bitzenetal., 1981;Findlayetal., 1981).
The amount ofparacetamolreceived by the sucklinginfant inafeedmaybecalculatedas a percentageof theweight-adjusted maternaldose received inthis studyor as apercentageof the lowest recommended infantsingledose. In order todo so it is assumed that:
a)the milk intakeis 150ml kg-' day-', as at peak lactation,
b)the infant suckles five timesaday, c) the maternal weight is 60 kgand
d)the lowest recommendedsingle infant doseis 60 mg(BritishNationalFormulary, 1986) Inthe volunteermothers(Methods,Subjects, a) the mean maximum concentration of para- cetamol in milkwas 10.3 ± 1.3 mg1'1andthe averageconcentrationwas6.1 ±0.8mgI-1. On thisbasis,aninfantsucklingonce atthe timeof peak milk paracetamol concentration would receive 1.85% (or on average 1.1%) of the weight-adjustedmaternalsingledose.Similarly, an infantwhich sucklesonce at thepeakpara- cetamol concentration would receive0.52% of the lowest recommended infant single dose.
Clearly these estimates may not be taken to apply when paracetamol is used in repeated doses andthereare noliteraturedataonwhich tobaseanestimate of the exposure of the infant toparacetamolunder suchconditions.
Thebiotransformation of paracetamol in the adultis wellestablished andthemajormetabo- lites arePG and PS (Prescott, 1980). A small proportionofthedrug(<10% ) is oxidised by the mixed function oxidase system to a reactive intermediate(s) which conjugates with hepatic glutathione and appears in the urine as para- cetamol cysteine (PC) and paracetamol mer- capturic acid (PM) (Mitchelletal., 1973, 1974;
Davisetal., 1976; Howieetal.,1977;Slattery&
Levy, 1979). Any oxidisedmetabolitethat does notcombinewithglutathione isapotential cause of celldamage. Inourstudyof six infants who receivedparacetamol in breastmilk, the parent drug,PG andPS were detectable intheurineof them all and PC and/or PM in 5. This finding contrastswith that of Berlinetal. (1980) who, alsousinganhigh performanceliquidchromato- graphicmethod ofanalysis,failedtodetect para- cetamol ormetabolites in the urine ofnursing infants. We found that the infants excreted a significantly higher proportion of unchanged paracetamol butalowerproportionofPS than did 49healthyvolunteerswho tookasingleoral doseof paracetamol(Table 2).Levyetal.(1975) who gave paracetamol 12 mgkg-1bymouthto neonatesandMilleretal.(1976)who gave 10 mg
kg-'found thathigherpercentagesof thedose were excreted assulphate thanasglucuronide.
These studies employed both a largerdose of paracetamol anda longer period ofurine col- lection than did the work we report; neither studygavedataonPCorPM. Ourfindingsthus differ from those previously reported and are compatible withadeficiencyofsulphate conju- gation bythe neonate, although immaturityof
in and neonate 67 renal function may also contribute to the dif-
ferences in the recoveries of paracetamol and of its metabolites between neonates andolder subjects.
Despitetheincreased excretion oftheparent drug, no significant increase was noted in the productsofcytochromeP-450oxidation (PC+
PM) suggestingthatthere maybe lower concen- trations or loweractivitiesof the mixedfunction oxidasesystem orglutathione transferasein neo- natesthan in older subjects.Therefore,ininfants, eithertheformation of the reactive metaboliteor itsdetoxication may be incompletelydeveloped.
There was asignificantincrease inthe amount of paracetamol (and milk) excreted from the
frequentlysampled breast compared with that recovered fromthe breast that was sampled only once. This suggests that the quantity ofpara- cetamolreceived in milk is dependent on milk flow and is a variable that should be taken into account in the design and interpretation of studies of drug passage into breast milk.
Theworkwassupportedby grantsfrom theArthritis Research Council and Wessex Regional Health Authority.We aregratefultoMrs K. M.Cordall for helpwith laboratoryassays and to Mrs S. J.Humphries fornursing assistance.
Adriaenssens, P. I. & Prescott, L. F. (1978). High performance liquid chromatographic estimation of paracetamol metabolites in plasma. Br. J. clin.
Berlin,C. M., Yaffe,S. J.&Ragni,M.(1980). Dispo- sition ofacetaminopheninmilk, saliva andplasma.
Bitzen, P.-O, Gustafsson, B., Jostell, K. G., Melander, A. &Wahlin-Boll,E.(1981). Excretion ofparacetamolin human breastmilk.Eur. J. clin.
Pharmac., 20, 123-125.
Davis, M., Simmons, C. J., Harrison, N. G. &
Williams,R.(1976). Paracetamol overdose inman:
relationship between pattern of urinary metabolites andseverityof liver damage. Quart. J. Med.,45, 181-191.
Findlay,J. W. A.,DeAngelis,R. L.,Kearney,M. F., Welch,R. M.&Findlay, J.M.(1981). Analgesic drugsinbreast milk andplasma. Clin. Pharmac.
Howie, D., Adriaenssens, P. I. & Prescott, L. F.
(1977). Paracetamol metabolism following over- dosage: application of high performance liquid chromatography.J.Pharm. Pharmac.,29,235-237.
Levy,G., Khanna,N.N.,Soda,D.M.,Tsuzuki, 0. &
Stern, L. (1975). Pharmacokinetics of acetamino- phen in thehuman neonate:formationof acetamino- phenglucuronide andsulfate in relationtoplasma bilirubin concentration and D-glucaric acidexcre- tion.Pediatrics,55,818-825.
Matheson, I. (1985). Drugs takenby mothers in the puerperium.Br.med. J., 290,1588-1589.
Miller, R.P., Roberts,R.J. &Fischer, L. J. (1976).
Acetaminophen elimination kinetics in neonates, adults and children. Clin. Pharmac. Ther., 19, 284-294.
Mitchell,J.R., Jollow,D.J., Potter,W.Z., Davis,D.
C., Gillette,J. R. &Brodie, B.B. (1973). Aceta- minophen-induced hepatic necrosis. 1. Role of metabolism.J.Pharmac.exp. Ther.,187,185-194.
Mitchell, J. R., Thorgeirsson, S. S., Potter, W. Z., Jollow,D.J.&Keiser,H.(1974). Acetaminophen- inducedhepatic injury:protective roleof glutathione inmanand rationale fortherapy. Clin. Pharmac.
Passmore,C., McElnay, J. C. & D'Arcy,P. F.(1984).
Drugs taken by mothers in the puerperium: in- patient surveyin Northern Ireland. Br. med. J., 289,1593-1596.
Prescott, L. F. (1980). Kinetics and metabolism of paracetamol andphenacetin. Br.J.clin.Pharmac., 10(Suppl. 2), 291-298S.
Rane, A.& Wilson, J. T.(1983). Clinical pharmaco- kinetics in infantsandchildren. InHandbook of clinical pharmacokinetics, eds Gibaldi, M. &
Prescott,L.F.,pp142-167. Balgowlah, Australia:
Slattery, J. T. & Levy, G. (1979). Acetaminophen kinetics in acutely poisoned patients. Clin. Pharmac.
(Received21July 1986, accepted 5 March 1987)