urinary excretion and metabolism of pethidine and norpethidine in

Br.J. Anaesth. (1977), 49, 891

URINARY EXCRETION AND METABOLISM OF PETHIDINE ANDNORPETHIDINE IN THE NEWBORN

M. I. J. HOGG, P. C. WIENER, M. ROSEN AND W. W. MAPLESON

SUMMARY

In seven neonates, whose mothers were given pethidine during labour, urine was collected for thefirst 24-40 h of life. Urinary volume and pH, and concentrations of pethidine and norpethidine inthe urine were measured. Urine flow rate was low for the first 7-22 h, and then high for about 12 h.The rate of excretion of pethidine and norpethidine was approximately parallel to the urine flow rate.Howeverj the ratio of the rate of excretion of norpethidine to that of pethidine increased with timeand the concentration of norpethidine in urine decreased first and then, after 18 h, increased signifi-cantly. These findings indicate that the neonate can metabolize pethidine, although the rate ofmetabolism is probably less than in the adult. The total amounts of pethidine and norpethidineexcreted in the first 24 h after birth were positively related to the dose-delivery interval in the motherfor intervals up to at least 5 h. From the data it is estimated that 95% of the total pethidine trans-ferred from the mother would be eliminated by the baby by the 2nd to 3rd day after birth.

Pethidine produces respiratory depression in theneonate (Koch and Wendel, 1968) and changes inbehaviour which may be discernible for days (Brack-bill et al., 1974; Wiener, Hogg and Rosen, 1977a, b)or even weeks (Richards and Bernal, 1972). Thisseems surprising since the pharmacological effects ofpethidine would not be expected to last so long;however, there are no data available on the rate ofexcretion of pethidine in the neonate. This informa-tion could have practical importance when deciding,for instance, whether or not to repeat the dose of anarcotic antagonist in a neonate.

Although pethidine and its metabolites, transferredfrom the mother, appear in neonatal urine (Way et al.,1949; Crawford and Rudofsky, 1965; O'Donoghue,1968, 1971) the evidence for metabolism of pethidineby the neonate is contradictory: Crawford andRudofsky (1965) failed to demonstrate metabolism intwo babies given pethidine i.m.; O'Donoghue (1968)did demonstrate metabolism but in one baby only.Consequently, the excretion kinetics of pethidine andnorpethidine have been measured in the newborn,from birth, following the administration of pethidineto the mother during labour.

METHODS

Babies of 37 mothers who had received pethidineduring the first stage of labour were studied. However,

M. I. J. HOGG, B.SC., P. C. WIENER, M.D., F.F.A.R.C.S.;

M. ROSEN, M.B., B.CH., F.F.A.R.C.S.; W. W. MAPLESON, D.SC,

F.INST.P.; Department of Anaesthetics, Welsh NationalSchool of Medicine, Heath Park, Cardiff CF4 4XN.

the practical difficulties of collecting urine were suchthat complete collections were obtained from onlyseven babies. All the neonates were delivered by thevertex, either spontaneously or easily by forceps, andhad an Apgar score greater than 7 at 1 min. Atdelivery, maternal venous blood and umbilical venousblood were taken for measurement of pethidineconcentration in plasma.

Urine was collected using a Hollister newbornU-bag attached for up to 48 h after birth. The bagwas fitted as soon as practicable after birth and carefulobservation made it almost certain that no urine waspassed between birth and the fitting of the bag.During the collection period the bag was inspectedfrequently by one of a team of nurses employed forthe study; if a leak was found or even suspected in thebag attached to any baby, that baby was excludedfrom the study. Urine was removed from the bagusing a sterile 10-ml syringe and the volume wasrecorded. The time was noted when the bag wasemptied, the urine pH recorded and the samplestored at — 24 °C. Each urine specimen was analysedfor pethidine and norpethidine concentration by gaschromatography. The method used was a modificationof that of Taylor (1968) and in our hands it had acoefficient of variation for pethidine in urine of 4.6%at 0.8 nmol. ml"1 and for norpethidine in urine of

RESULTS

All the neonates were male. Table I summarizessome of their characteristics. Five mothers had been

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892 BRITISH JOURNAL OF ANAESTHESIA

TABLE I. Maternal pethidine dose, plasma concentrations at delivery, birth weight, urine pH and timing of urine collections inseven neonates

Subject

1234567

MeanSD

Maternalpethidine

dose (mmol)

*0.455 i.v.0.529 i.m.

*0.705 i.v.0.352 i.m.0.529 i.m.0.529 i.m.0.529 i.m.

0.5180.106

Dose-deliveryinterval (h)

1.83—2.651.835.035.17

3.301.68

Birthweight(kg)

3.502.903.293.443.333.943.61

3.430.32

Pethidine plasmaconcn (nmol. ml"1)

MVt

0.933.072.220.731.741.541.78

1.700.81

UVf

0.932.021.500.731.332.141.58

1.450.53

UV/MV

1.000.660.671.000.771.400.89

0.910.26

Mean•

urinePH7.27.0—

6.97.26.26.1

6.770.49

Time (h)

Delivery tobluiL UI1X1C

collection

0.850.831.000.850.701.250.88

0.910.17

Start to|npt

Idol

collection

38.039.030.547.523.842.841.3

37.68.0

* Total dose of i.v. pethidine by patient demand,f MV = maternal venous; UV = umbilical venous.

given pethidine by i.m. injection and the other twoused a slow-i.v.-injection self-administration method(Evans et al., 1976). The doses of pethidine, the dose-delivery intervals and the neonatal birth weights weretypical of those in this hospital (Evans et al., 1976).Maternal and umbilical plasma concentrations ofpethidine and the umbilical/maternal ratio weresimilar to those in other reports (O'Donoghue, 1968;Taylor, 1968). Mean urine pH was slightly acidic.(Fluctuations within each neonate were small.) Withthis small group of neonates no relationship wasapparent between any of the measured variables andthe dose of pethidine or the dose-delivery intervalexcept for a suggestion that long intervals wereassociated with more-acid urine.

In all instances urine collection was started within1.25 h after birth. In adult studies the times of collec-tion of urine are the times of micturition; but to havemade collections at micturition in the neonate wouldhave necessitated continuous observation of thecollection bag. In order to approach this ideal the bagwas inspected at frequent, usually half-hourly,intervals. For each emptying of the collection bag thevolume of urine it contained, and the amounts ofpethidine and norpethidine therein, were divided bythe time since the last emptying (the "collectionperiod") to yield rates of excretion.

Since the collection periods varied, the followingprocedure was adopted to derive average excretionrates. For each neonate cumulative excretions ofpethidine, norpethidine and urine were plottedagainst time from fitting the collecting bag (forexample fig. 1). Assuming that in a collection period

the rate of excretion is constant, each consecutivepair of points can be joined by a straight line. At anytime, therefore, the amount of urine excreted can beestimated from the graph. For instance, in the interval

Cumulative excretionof urine

(ml)

60

40

20

12 24 36I

48

Time (h)FIG. 1. Cumulative excretion of urine in a neonate (no. 7)plotted against time after fitting collecting bag (approxi-

mately 1 h after birth).


PETHIDINE AND NORPETHIDINE IN THE NEWBORN 893

18-21 h, 17.2 ml of urine is the estimated excretion,giving a mean rate of excretion for that 3-h period of5.7 ml. h"1.

For each neonate, the rates of excretion of urine,pethidine and norpethidine, averaged over each 3-hperiod, were derived in this manner and then averagedover the group. From these rates the cumulativeexcretions and the average concentrations (for each3-h period) of pethidine and norpethidine werederived for each individual and then these also, withthe corresponding rates of excretion, were averagedover the group. The rates of excretion of urine,pethidine and norpethidine are plotted against timefrom fitting the collecting bag for a typical individualin figure 2 and for the average neonate in figure 3. In

Rate of excretion

1000

PethidineNorpethidine

100

Rate of excretion| 0 Q nmol.h")

10

PethidineNorpethidine

/N.

10

Rate of Urineexcretion (ml. h"1)

01

X..

12 36 48

Rate of Urineexcretion (ml. h~

10

24Time (h)

FIG. 3. Average rates of excretion of pethidine, norpethi-dine and urine (on logarithmic scales) plotted against time.

both figures there is a remarkable parallelism betweenthe rates of excretion of pethidine and norpethidineon the one hand and that of urine on the other.

Usually for several hours no urine was passed and ineach individual there was a period of 9-12 h duringwhich the excretion rate was relatively high, but thetime at which this period started varied from 6 to 18 h;the net effect of this on the graph of average data is toindicate an extended period of moderately high urineflow rate not seen in any individual. A similar patternfor excretion of pethidine and norpethidine is seen also.The average data for the period after 39 h are based on

__i only two cases and are therefore not very reliable.48 The fluctuations in the rate of excretion of pethi-

dine (figs 2 and 3) make it impossible to use theFIG. 2. Rates of excretion of pethidine, norpethidine and conventional method of kinetic analysis by fitting anurine (on logarithmic scales) in a neonate (no. 7), plotted exponential equation to the rate of excretion of drug

against time. against time. However, it was found that concentration

0112 24

Time (h)36



TABLE I I . The amplitude and time constants of the exponential equation of pethidineconcentration against time in each neonate and for the average data

Subject

1234567

Mean data

Amplitudeconstant

(nmol. ml"1)

40.142.624.223.4

5.779.367.4

38.8

Timeconstant

(h)

32.310.014.914.145.416.127.0

20.7

No. ofsamples

6557488

15

Fratio

1.660.932.38.80.5

150.212.1

39.0

P

0.30.0040.010.030.50.000020.01

0.00003

Concentration (nmol. ml"1)

50 -

Pethidine Content5000,- (nmol)

FIG. 4. Average urine concentration of pethidine and nor- FIG. 5. The amount (on a logarithmic scale) of pethidinepethidine plotted against time. A single exponential curve that remains to be excreted by each neonate plotted againstfor pethidine and a weighted cubic polynomial for norpethi- *'"r"1

dine are shown.time.



Pelhidine Content

5000 r (nmo))

1000

500

100

50

1012 24

Time (h)36 48

FIG. 6. The average amount (on a logarithmic scale) ofpethidine that remains to be excreted plotted against time.

of pethidine in the urine declined fairly consistentlywith time. Therefore, a single exponential equationwas fitted to the data for each individual; in five, theexponential was statistically significant (table II). Inthe others, pethidine concentration was almost con-stant (no. 5) or decreased rapidly only after 18 h (no.1). An exponential derived from the mean data (fig.3), obtained by dividing mean pethidine excretionrates by mean urine excretion rates and obtainingmean pethidine concentration against time, is highlysignificant (P = 0.00003), with a time constant of20.7 h (fig. 4).

Norpethidine concentration did not decline ex-ponentially with time. Polynomial equations (up to acubic) were fitted to the fluctuations in norpethidineconcentration but, in individuals, the scatter in thedata was too great for any of them to be significant.However, for the average data (fig. 4) a cubic equation

(taking account of sample frequency (Armitage, 1971))gave a significant fit (P = 0.03). The fitted curve showsthat norpethidine concentration decreased at first andthen increased to a peak between 30 and 35 h beforedecreasing again.

Therefore, pethidine concentration in neonatalurine decays exponentially with time, whereas nor-pethidine concentration exhibits a decrease, anincrease and then a further decrease.

The cumulative excretion of pethidine can beappreciated by plotting the total amount of pethidineremaining to be excreted by any time, against time.This was done for all individuals in figure 5 and forthe average in figure 6. In figure 5, the initial slowdecline (because of low urine flow) was followed byrapid excretion. The average data (fig. 6) showed asimilar but smoother pattern with the excretion rateremaining almost constant after 12 h. An exponentialequation fitted to the data from 12 h on was highlysignificant (P = 2 x 10~9) with a time constant of 10 h.

DISCUSSION

The results confirm that, following maternal adminis-tration of pethidine during labour, both pethidine andnorpethidine are excreted in neonatal urine. Integra-tion of the rates of excretion in figure 3 indicated that,in the first 24 h, the average neonate excreted 809nmol of pethidine and 356 nmol of norpethidine.Expressing these figures as percentages of the mater-nal dose of pethidine facilitates a comparison with theresults of other authors who administered varyingdoses of pethidine (table III). Way and colleagues(1949) reported a percentage excretion of pethidinesimilar to ours in similar circumstances although, inview of their assay method (table III), their figure forpethidine may include some norpethidine. Crawfordand Rudofsky (1965) and O'Donoghue (1968, 1971)obtained greater percentage excretions after smallerdoses, but in the work of Crawford and Rudofskythere were further differences of circumstance: i.v.injection, much shorter dose-delivery intervals andlonger collection periods; also their assay methodmay not have reliably separated pethidine and nor-pethidine (Taylor, 1968).

Dose-delivery intervalO'Donoghue (1968) divided her data into three

groups based on dose-delivery interval (table III).Although no statistical analysis is possible, since datafor individuals were not given and the numbers ineach group were small, it is apparent that, for bothpethidine and norpethidine, the mean amounts



TABLE I I I . Excretion of pethidine and norpethidine after birth in the urine of babies whose mothers received pethidine

Maternal dose ofpethidine

RouteDose-delivery intervalDuration of collectionNo. of neonates% pethidine dose excreted:

meanSD

% norpethidine doseexcreted: meanSD

Method of analysis

Way and others(1949)

0.35-0.70 mmol(100-200 mg)

i.m.1st stage

24 h9

0.13(0.2)

—Methyl-orange

dye-binding

Crawford and Rudofsky O'Donoghue(1965)

0.18 mmol(50 mg)

i.v.0.05-0.55 h

48 h11

0.3(0.26)

0.08(0.13)

Methyl-orangedye-binding

(1968)

0.18 mmol(50 mg)

i.m.1 h 2.5 h 6 h

24 h 24 h 24 h3 8 3

0.18 0.22 0.34(0.05) (0.13) (0.16)

0.06 0.14 0.20(0.04) (0.09) (0.13)

Thin-layer chromatographyand methyl-orange dye-binding

Present study

0.52 (SD 0.11) mmol(147 (SD 30) mg)

i.m./multiple i.v.1.83-5.17 h

24 h7

0.13(0.12)

0.04(0.02)

Gas-liquidchromatography

excreted increased with dose-delivery interval.Regression analysis of Crawford and Rudofsky's(1965) data reveals a significant positive relationshipbetween the amount of pethidine excreted y (nmol)and the dose-delivery interval t (h) for intervals of upto 0.55 h: y = 3134*4-27; P = 0.0009. In our studyneonates, whose mothers were given pethidine 0.53mmol (150 mg) i.m., excreted, during the first 24 hafter delivery, amounts of pethidine and norpethidinewhich increased significantly with dose-deliveryinterval for intervals of up to 5 h: for pethidine, y =438*-384; P = 0.002; for norpethidine, y = 69*+15; P = 0.04. Although it is surprising that otherauthors have not considered this aspect of theirresults, it seems quite clear that, after an injection ofpethidine to the mother, uptake of pethidine by thefoetus continues for at least 5 h.

This finding seems to conflict with the usualteaching (Bonica, 1967; Shnider, 1970; Crawford,1972) that, following i.m. pethidine, peak depressionin the newborn occurs if the baby is delivered between1 and 4 h after administration and, conversely, thatnarcotic depression will be minimal if a baby isdelivered before 1 h or more than 4-6 h after injec-tion. This is based on assessments of short-termdepression (such as the Apgar score at 1 min and thetime to sustained ventilation). However, it is clearfrom our study that the total amount of pethidinetransferred to the foetus increases with dose-deliveryinterval up to at least 5 h. Therefore, even if short-term depression is not detectable at this dose-delivery interval (5 h) more subtle but longer-term

changes detected by neurobehavioural assessment(for example, Brackbill et al., 1974; Wiener, Hogg andRosen, 1977a, b) may be more dependent on the totalbody content of pethidine and may, therefore, beaffected even with dose-delivery intervals of 5 h ormore. Accordingly, it should not be concluded thatdose-delivery intervals greater than 4 h prevent allpharmacological effects in the neonate.

MetabolismO'Donoghue (1968) administered pethidine 0.035

mmol (1 mg) to one neonate whose mother hadreceived no medication during labour and, using thin-layer chromatography, found pethidine (780 nmol),and two metabolites, norpethidine (60 nmol) andpethidinic acid (220 nmol), in the urine collected over24 h. Crawford and Rudofsky (1965), in a similarstudy in two neonates, collected urine for 48 h butfound only pethidine (1050 nmol, 1580 nmol) in theurine, although the failure to detect metabolites mayhave been because of a lack of sensitivity and specifi-city of the methyl-orange method used (Taylor, 1968).

In the present study, aveiage norpethidine concen-tration in urine showed a significant increase between30 and 35 h (fig. 4). This suggests that, in addition toexcreting norpethidine of maternal origin, the new-born is metabolizing pethidine to form norpethidine.This suggestion is supported by the followingargument.

Since norpethidine is more polar than pethidine,its tubular reabsorption will be less and therefore itsrate of excretion will almost certainly be greater than



that of pethidine. Therefore, if the newborn wereunable to produce norpethidine, that of maternalorigin would be rapidly excreted and the ratio of nor-pethidine to pethidine would decrease with time. Yetin every neonate the ratio in fact increased, usuallysignificantly (0.1 >P> 0.0006). However, with oneexception (no. 3) the slope of ratio against time wasless than 0.08 h"1, whereas a similar analysis ofTaylor's (1968) data, for adults given pethidine 0.18mmol (50 mg) i.v., gave a mean slope of 0.226 h~x,that is nearly three times as great as in our neonates.This argument confirms that the neonates can meta-bolize pethidine but the rate of n-demethylation tonorpethidine is probably less than found in adults, asmight be anticipated from less efficient neonatalhepatic function (Beckett, 1973).

Excretion kinetics in adult and neonateFor neonates in the present study, with normal

uncontrolled urine pH, the rate of excretion ofpethidine was markedly dependent on urine flow rate(figs 2 and 3) and did not decline exponentially. InTaylor's (1968) study, in adults with controlled acidurine pH, the rate of pethidine excretion declinedrelatively smoothly and exponentially with time,even though urine flow rate varied over a range ofapproximately 5 : 1 in each individual. This suggeststhat the processes governing excretion in neonatesmay be different from those operating in Taylor'sadult study.

If the concentration of pethidine in urine (insteadof pethidine excretion rate) is plotted against time, thedistribution of Taylor's observations in adults isbroadly similar to that shown for our neonates infigure 4 and can be fitted by a single exponential. Theimportance of urine flow rate in the excretion processwas then assessed as follows. For each measurementthe ratio, of the measured concentration of pethidineCm to the corresponding concentration read from thefitted exponential Ce, was calculated. The linearregression of CjJC,, on urine flow rate was thencalculated.

In the adults (Taylor, 1968) the slope of theregression, of CmjCe on urine flow rate, was alwaysnegative and in two of the three subjects was signifi-cant (P = 0.0025,0.00002). In only three of the sevenneonates was the slope negative and in only one ofthese was it significant (P = 0.004). In the other six,P ranged from 0.1 to 0.75. Therefore, in general forneonates, an increase in urine flow rate produced nochange in urine pethidine concentration but didproduce an increase in the rate of pethidine excretion.

Conversely for adults, an increase in urine flow rateproduced a decrease in urine pethidine concentrationbut no change in the rate of pethidine excretion. Apossible explanation of these differences is as follows.

For the adults, increases in urine flow rate wereprobably a result of fluid intake producing a reductionin the amount of plasma water reabsorbed in the renaltubules, with little or no change in glomerularfiltration rate (GFR). Therefore the rate of excretionof pethidine from plasma to glomerular nitrate(GFR x free-pethidine plasma concentration) wouldremain essentially constant. Furthermore, underconditions of acid urine pH, almost all the pethidinein the urine would be ionized and unavailable for re-absorption. Therefore, if the rate of reabsorption ofwater at the tubules decreases, urine flow increasesand pethidine concentration in the urine decreases butthe rate of excretion of pethidine changes little.

In our neonates, at least part of the increase in urineflow rate may be attributed to an increase in glomeru-lar filtration rate following an increase in renal bloodflow (Oh, Oh and Lind, 1966). Therefore, if there isno change in the fraction of water reabsorbed, anincrease in urine flow rate would produce no changein urine pethidine concentration, but would producean increase in the rate of excretion. Even if the fractionof water reabsorbed increases following an increase inglomerular filtration rate, or following feeding as inadults, there would still be little change in urinepethidine concentration because, with the urine pHfound under normal conditions, less of the pethidinewould be ionized and more would be available forreabsorption.

Time for elimination of pethidineIn adults, plasma concentrations in normal

volunteers decline according to two exponentials, theslower of which has a time constant of about 5 h(Klotz et al., 1974; Mather et al., 1975; Stambaughet al., 1976); accordingly elimination would be 95%complete in less than 15 h.

In the neonate, the time for elimination of pethidinecan be estimated from the present data in two ways.Using the plot of concentration in urine against timefor the average data (fig. 4) an exponential curve witha time constant of 20.7 h was obtained. On this basis,assuming body burden to be approximately propor-tional to concentration in urine, 95% of the drugwould be eliminated in approximately 62 h (threetime constants). An alternative method (fig. 6) pro-vides an exponential with a time constant of only 10 h.However, this latter time constant applies only during



the period of high urine excretion rate. In the first12 h there is little excretion (fig. 6) and, after theperiod of high urine excretion, the pethidine excretionrate can be expected to decrease, as can be seen insome individuals in figure 5. Therefore, a lower limitto the time for 95% elimination of the pethidinewould be set by 12 h plus three 10-h time constants,that is 42 h. Therefore, by the 3rd day (between 42and 62 h) there should be little pethidine remainingin the body to exert any pharmacological effect. Itseems unlikely, therefore, that effects seen in neonatesmuch beyond the 3rd day of life (Richards andBernal, 1972) could be a result of a direct pharma-cological action of pethidine or its metabolites andsome other explanation may be necessary. On theother hand, it has been demonstrated that the effectsof pethidine on ventilation and feeding are apparentfor up to 48 h after birth (Wiener, Hogg and Rosen,1977a, b). Therefore, if it is considered desirable toreverse these effects of pethidine in the newborn bythe administration of a narcotic antagonist, it may benecessary to continue the administration for up to 3days.

ACKNOWLEDGEMENTS

We thank Professor M. D. A. Vickers for his advice, MissesMichelle Bird and Judith Bourge for their meticulousperformance of the analyses, and the paediatricians andnursing staff of the University Hospital of Wales for theirwilling co-operation. The study was supported by a grantfrom the Medical Research Council.

REFERENCES

Armitage, P. (1971). Statistical Methods in Medical Research,p. 319. Oxford: Blackwell.

Beckett, A. H. (1973). Maternal and neonatal metabolism ofanalgesic drugs. Br. J. Anaesth., 45, 770.

Bonica, J. J. (1967). Principles and Practice of ObstetricAnalgesia and Anesthesia, Vol. 1, p. 203. Philadelphia:F. S. Davis.

Brackbill, Y., Kane, J. Maniello, R. I., and Abramson, D.(1974). Obstetric meperidine usage and assessment ofneonatal status. Anesthesiology, 40, 116.

Crawford, J. S. (1972). Principles and Practice of ObstetricAnaesthesia, 3rd edn, p. 75. London: Blackwell.

Rudofsky, S. (1965). The placental transmission ofpethidine. Br. J. Anaesth., 37, 929.

Evans, J. M., Rosen, M., McCarthy, J., and Hogg, M. I. J.(1976). Apparatus for patient-controlled administrationof intravenous narcotics in labour. Lancet, I, 17.

Klotz, U., McHorse, T. S., Wilkinson, G. R., and Schenker,S. (1974). The effect of cirrhosis on the disposition andelimination of meperidine in man. Clin. Pharmacol. Ther.,16. 667.

Koch, G., and Wendel, H. (1968). The effect of pethidineon the postnatal adjustment of respiration and acid-basebalance. Ada Obstet. Gynaecol. Scand., 47, 27.

Mather, L. E., Tucker, G. T., Pflug, A. E., Lindop, M. J.,and Wilkerson, C. (1975). Meperidine kinetics in man.Clin. Pharmacol. Ther., 17, 21.

Morrison, J. C , Wiser, W. I., Rosser, S. I., Gayden, J. O.,Bucovoz, E. T., Whylerew, W. D., and Fish, S. A. (1974).Metabolites of meperidine related to fetal depression.Am. J. Obstet. Gynecol., 118, 1132.

O'Donoghue, S. E. F. (1968). An investigation of thedistribution of pethidine and chlorpromazine in maternal,fetal and biological fluids. Ph.D. Thesis, Trinity College,Dublin.

(1971). Distribution of pethidine and chlorpromazinein maternal fetal and neonatal biological fluids. Nature(Lond.),229,124.

Oh, W., Oh, M. A., and Lind, J. (1966). Renal function andblood volume in newborn infants related to placentaltransfusion. Acta Paediatr. Scand., 56, 197.

Richards, M. P. M., and Bernal, J. F. (1972). Effects ofobstetric medication on mother-infant interaction andinfant development; in Psychosomatic Medicine inObstetrics and Gynaecology (ed. N. Morris), p. 303. Basel:S. Karger.

Shnider, S. M. (1970). Obstetrical Anesthesia: CurrentConcepts and Practice, p. 46. Baltimore: Williams andWilkins.

Stambaugh, J. E., Wainer, I. W., Sanstead, J. K., andHemphill, D. M. (1976). The clinical pharmacology ofmeperidine. J. Clin. Pharmacol., 16, 245.

Taylor, J. F. (1968). Metabolic and stereochemical studiesof some analgesics. Ph.D. Thesis, University of London.

Way, E. L., Gimble, A. I., McKelway, W. P., Ross, H.,Sung, C , and Ellsworth, H. (1949). The absorption,distribution and excretion of isonipecaine (Demerol).J. Pharmacol. Exp. Ther., 96, 477.

Wiener, P., Hogg, M. I. J., and Rosen, M. (1977a). Theeffects of intravenous naloxone on pethidine-induced neo-natal depression. Br. Med.J. (in press).

(1977b). The effects of intramuscularnaloxone on pethidine-induced neonatal depression. Br.Med.J. (in press).

EXCRETION URINAIRE ET METABOLISME DELA PETHIDINE ET DE LA NORPETHIDINE CHEZ

LE NOUVEAU-NE

RESUME

On a recueilli pendant les premieres 24-40 h de leur vie,Purine de sept nouveaux-nes, dont les meres avaient recu dela pethidine pendant le travail. On a mesure le volumeurinaire et le pH, de meme que les concentrations depethidine et de norpethidine dans Purine. Le debit d'urinea ete faible pendant les 7 a 22 premieres heures, puis elevependant environ 12 h. Le taux d'excretion de la pethidine etde la norpethidine a ete a peu pres parallele au debit d'urine.Cependant, le taux d'excretion de la norpethidine parrapport a celui de la pethidine a augmente avec le tempsalors que la concentration de norpethidine dans Purine ad'abord diminue, puis, apres 18h, augmente d'une manieresignificative. Ces observations impliquent que le nouveau-ne peut metaboliser la pethidine, bien que son taux demetabolisme soit probablement plus faible que celui dePadulte. Les quantites totales de pethidine et de norpethi-dine excretees pendant les 24 premieres heures qui ont



suivi la naissance ont ete positivement reliees a l'intervalle"administration de la dose/accouchement" de la merepour des intervalles allant jusqu'a au moins 5 h. A partirdes donnees, on a estime que 95% du total de la pethidinetransferee par la mere sont elimines par le bebe dans les2 ou 3 jours qui suivent la naissance.

URINAUSSCHEIDUNG UND STOFFWECHSELVON PETHIDIN UND NORPETHIDIN BEIM

NEUGEBORENEN KIND

ZUSAMMENFASSUNG

Bei sieben Neugeborenen, deren Mutter wahrend derWehen Pethidin erhalten hatten, wurde wahrend derersten 24-40 Lebensstunden Urin gesammelt. Urinmengen,pH, sowie Pethidin- und Norpethidinkonzentrationen imUrin wurden gemessen. Die Urinausscheidung war in denersten 7-22 Stunden gering, danach fiir etwa 12 Stundenhoch. Die Absonderungsrate von Pethidin und Norpethidinwar etwa parallel zur Urinausscheidungsrate. Das Verhaltniszwischen Norpefludin- und Pethidinausscheidung erhohtesich jedoch im Lauf der Zeit, und die Norpethidinkonzen-tration im Urin sank zuerst, stieg aber nach 18 Stundenwesentlich an. Diese Ergebnisse zeigen, dass das Neuge-borene Pethidin im Stoffwechsel zu verarbeiten vermag,wenn auch in geringerem Masse als Erwachsene. DieGesamtmengen des ausgeschiedenen Norpethidins undPethidins in den ersten 24 Stunden nach der Geburtstanden in klarem Zusammenhang zu dem Intervallzwischen Verabreichung der Drogen an die Mutter undder Geburt—bei Intervallen von bis zu wenigstens 5

Stunden. Von den erhaltenen Daten wird geschatzt, dass95% der an die Mutter verabreichten Pethidinmenge vondem Neugeborenen bis zum zweiten oder dritten Tag nachder Geburt eliminiert wird.

EXCRECION DE ORINA Y METABOLISMODE PETIDINA Y NORPETIDINA EN EL

RECIEN NACIDO

SUMARIO

En siete neonatos, cuyas madres recibieron petidina duranteel parto, se recolecto orina durante las primeras 24 a 40 horasde vida. Se midieron el volumen de orina y pH y concen-traciones de petidina y norpetidina en la orina. La cantidadde orina resulto baja en las primeras 7 a 22 h, luego altadurante aproximadamente 12 h. La cantidad de excresionde petidina y norpetidina fue aproximadamente paralela a lade orina. Sin embargo, la relation de la cantidad de excresi6nde norpetidina comparada con la de petidina aument6 con elpaso del tiempo y la concentration de norpetidina en laorina disminuyo primero y luego, al cabo de 18 h, aumentoen forma significativa. Estos datos indican que el neonatopuede metabolizar petidina, aunque el grado de metabolismoprobablemente sea menor que en el adulto. Las cantidadestotales de excreci6n de petidina y norpetidina en lasprimeras 24 h siguiendo el parto estaban directamenterelacionadas al intervalo entre dosis y parto en la madre enintervalos de hasta por lo menos 5 h. De los datos obtenidosse estima que un 95% del total de petidina transferida de lamadre seria eliminado por el bebe al segundo o tercero dia denacido.


urinary excretion and metabolism of pethidine and norpethidine in

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