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Chapter 4. Determinants of drug disposition in infants

Chapter 4. Determinants of drug disposition in infants

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Determinants of drug disposition in infants



drugs. In fact, the gastric pH is 6-8 at birth, remains high during the first few weeks

of Iife (1) and attains adult values only after the age of 3 years. Gastrointestinal

motility is irregular in the neonate and slow gastric emptying may affect the timecourse but not the degree of drug absorption. The gastrointestinal tract of the newborn is rapidly colonised by microorganisms, some of which are capable of deconjugating drug metabolites that are secreted in the bile to release active drug.

The rate constant k is the fraction of the amount of drug in the body that is

eliminated in unit time. It reflects the sum of the contributions to elimination from

hepatic metabolism, renal excretion and biliary excretion. In subprimate mammals,

drug oxidising capacity generally presents postnatally, whereas the human fetus can

oxidise drugs and other xenobiotics already in the first trimester (2). The capacity

to inactivate foreign compounds by metabolism may generally be considered an

advantage although the same processes may transform some xenobiotics into active

or even toxic metabolites (3). The rate constant k may also be thought of as the

fraction of the total distribution volume (Vd) from which drug is completely cleared

in unit time and this provides a pharmacokinetic expression for clearance (C1)

C1 = k x Vd



(ii)



C1 is a useful measure of elimination capacity and is expressed as the volume of

blood or plasma cleared in unit time. From equation (i) its relation to steady state

drug concentration is:



C~s



F•

CI•



= ~



(iii)



The half-life (tl/2) of a drug in plasma is a poor, yet often used, estimate of elimination capacity. Clearance is a better indicator. The relation between them is:

tl/2



=



0.693 • Vd

C1



(iv)



This equation shows that tll 2 is a function of the drug's distribution as well as of

clearance. The t~/2 reflects the elimination capacity only if Vd remains constant. Vd

may change rapidly in the neonatal period with alteration in body composition (4)

and with changes in binding to plasma proteins. Therefore, clearance is the preferred method of comparing elimination capacity between children of different

ages. Nevertheless, drug half-lives are quoted in this chapter, as most information

in the literature is presented in this form.

60



Determinants of drug disposition in infants



HEPATIC CLEARANCE

The metabolic activity of the hepatocyte, the hepatic blood flow and the binding to

plasma proteins are the major determinants of drug clearance in the liver (5, 6).

Drugs cleared by liver metabolism are often classified into: (a) those that have a

low extraction in a single pass through the liver, i.e. the rate of metabolism by hepatocytes determines their inactivation, and (b) those that are extensively extracted,

i.e. the rate at which they are presented to the liver in the blood, namely hepatic

blood flow, is the important determinant of the clearance. Examples of group (a)

include phenytoin (7), tolbutamide, warfarin (8) and carbamazepine (9). Drugs of

group (b) include acetylsalicylic acid, morphine (7), pethidine (10), some tricyclic

antidepressants (11, 12), and lignocaine (lidocaine) (13). In general, drug metabolic

reactions initially involve molecular modification through oxidation, reduction or

hydrolysis; the drug metabolite may then be conjugated with various endogenous

water-soluble molecules and the resulting polar compound is then excreted by the

kidney. Drug disposition data relevant to infants in respect of these metabolic reactions appear in Tables 1 and 2.



Low extraction drugs

Drugs such as amobarbital and tolbutamide have a longer tl/2 in newborn infants

than in adults due to a lower rate of oxidation in the newborn (Table 1). If the drug

has been used by the mother throughout pregnancy, transplacental induction of the

fetal drug-metabolising enzymes may have taken place so that the t~/2 in the newborn approaches the same value as in the adult (cf. phenytoin and carbamazepine in

Table 1). It has long been known that children under 30 kg body weight (29) and

newborn infants (30) require higher weight-related doses of phenytoin than adults

to achieve similar plasma concentrations. The Vd of phenytoin is similar in newborn

infants and adults (31).



Intermediate-to-high extraction drugs

The disposition of these drugs is poorly studied in infants. Plasma concentrations of

propoxyphene and propranolol exhibit interindividual variation in children (32) and

the t~/2 of propoxyphene is similar in children and adults (15).



Drugs that are conjugated

The capacity to conjugate is often deficient in the newborn; the tl/2 values of oxazepam and bilirubin, which are glucuronidated, are respectively 3-4 times and 3-6

times longer in neonates than in adults (33, 34). Bromosulfophthalein is conjugated

with glutathione and cysteine and has a t~/2 in the neonate that is twice that in older

61



Determinants of drug disposition in infants

TABLE 1



Plasma half-lives in newborns and adults of drugs that are metabolised by oxidation



Drug name



Newborns (N) (h)



Adults(A) (h)



N/A



Reference



Aminopyrine

Amobarbital

Bupivicaine

Caffeine

Carbamazepine

Diazepam

lndometacin

Mepivacaine

Nortriptyline

Pethidine

Phenytoin

Theophylline

Tolbutami de



30-40

17-60

25

95

8-28

25-100

14-20

8.7

56

22

21

24-36

10-40



3-4

12-27

1.3

4

21-36

15-25

2-11

3.2

18-22

3-4

11-19

3-9

4.4-9



>1

>1

>1

>1

1

>1

>1

>1

>1

>1

1

>1

>1



(16)

(17)

(18)

(19)

(20)

(21 )

(22)

(14)

(23)

(24)

(26)

(27)

(28)



infants (35, 36). Conjugation with glycine and sulphate also occurs, e.g. with salicylic acid and paracetamol (acetaminophen). The developmental pattern of these

pathways is illustrated in Table 2.

Binding to plasma proteins

Several drugs are less bound to proteins in infant or umbilical cord plasma than in

adult plasma (Table 3). Displacement of drugs from protein-binding sites may be

caused by endogenous substances such as bilirubin (46) or free fatty acids (52), and

possibly by qualitative differences in albumin. The possible consequences of reduced binding are mostly related to drugs with low hepatic extraction; as more of

the unbound fraction is available for metabolism a lower total plasma concentration

can be expected. This may partly explain the low steady state plasma concentrations of phenytoin (low drug extraction) in young infants. In contrast, alterations in

binding do not limit the clearance of drugs that are extensively extracted by the

liver.



TABLE 2



Age-dependent metabolism and kinetics of salicylic acid and paracetamol



Drug



Conjugated

with



Urinaryexcretion (%)

Newborns



Salicylic acid

Paracetamol



62



75

Glycine

Glucuronic acid 10

Glucuronic acid 13-18

Sulphate

48-50



Plasma tl/2 (h)



Older

infants



Adults



Newborns



32-47

30-43



40-50

35

50-72

15-30



4.0-11.5

3.5



Older

infants



1-3.5



Adults



Determinants of drug disposition in infants



TABLE 3 Drugs with lower plasma protein binding in cord (or infant) serum than in adult serum

Drug group

Antibiotics

Antimicrobials

Cardiac glycosides

Anxiolytics

Tricyclic antidepressants

Analgesics

Local anaesthetics

Sedatives

Antiepileptics



Ampicillin, benzypenicillin (38), nafcillin (39)

Sulfamethoxypyrazine (40), sulfaphenazole (41), sulfadimethoxine,

sulfamethoxydiazin (42)

Digoxin (43)

Diazepam (44)

lmipramine (45), desmethylimipramine(46)

Salicylates (47), phenylbutazone (25)

Bupivicaine, lidocaine (48)

Pentobarbitone (50), phenobarbital (49)

Phenytoin (26), clonazepam (51)



Reprinted from Rane (37), by courtesy of the Publishers.



RENAL CLEARANCE

Glomerular filtration and tubular secretary processes are functionally immature at

birth (53, 54) and during the first year of life. Calculations show that a drug distributed in the extracellular water and eliminated only by glomerular filtration

would have a t~/2 of 100 min in a 1.5-month-old infant but only 67 min in an adult;

if the drug were eliminated only by tubular secretion the fin would be 40 min in this

infant and 13 min in an adult (55). Due caution must thus be exercised in the use of

drugs that are excreted in the kidneys, e.g. aminoglycoside antibiotics and digoxin.

CONCLUSION

Physiological maturation with increasing age has a significant influence on drug

bioavailability and distribution, and on hepatic and renal clearance, which are important determinants of steady state drug concentrations in plasma. These changes

are particularly pronounced in early infancy when a child is likely to be breastfed.

In addition, the type of drug, e.g. whether it is metabolised or excreted directly in

the kidneys, must be taken into account in the assessment of the consequences of

drug intake via the breast milk.

REFERENCES

1. Weber WW, Cohen SN (1975) Aging effects and drugs in man. In: Gillette JR, Mitchell JR,

(Eds) Concepts in Biochemical Pharmacology, pp 213-233. Springer Verlag, New York.

2. Yaffe SJ, Rane A, Sj6qvist F, Bor6us LO, Orrenius S (1970) The presence of a mono-oxygenase

system in human fetal liver microsomes. Life Sci., 9, 1189-1200.

3. Drayer DE (1982) Pharmacologically active metabolites of drugs and other foreign compounds.

Clinical, pharmacological, therapeutic and toxicological considerations. Drugs, 24, 519542.



63



Determinants of drug disposition in infants

4. Friis-Hansen B (1961) Body water compartments in children: changes during growth and related

changes in body composition. Pediatrics, 8, 169-181.

5. Wilkinson GR (1975) Pharmacokinetics of drugs disposition: hemodynamic considerations. Ann.

Rev. Pharmacol., 15, 11-27.

6. Wilkinson GR, Shand DG (1975) A physiological approach to hepatic drug clearance. Clin.

Pharmacol. Ther., 18, 377-390.

7. Rowland M, Blaschke TF, Meffin PJ (1976) Pharmacokinetics in disease states modifying hepatic and metabolic function. In: Benet LZ (Ed) Effect of Disease States on Drug Pharmacokinetics, pp 53-76. American Pharmaceutical Association, Washington DC.

8. Andreassen PB, Vesell ES (1974) Comparison of plasma levels of antipyrine, tolbutamide and

warfarin after oral and intravenous administration. Clin. Pharmacol. Ther., 16, 1059-1065.

9. Rane A, Shand DG, Wilkinson GR (1977) Disposition of carbamazepine and its 10,11-epoxide

metabolite in the isolated perfused rat liver. Drug Metab. Dispos., 5, 179-184.

10. Nies AS, Shand DG, Wilkinson GR (1976) Altered hepatic blood flow and drug disposition.

Clin. Pharmacokinet., 1, 135-155.

11. Gram LF, Christiansen J (1975) First-pass metabolism of imipramine in man. Clin. Pharmacol.

Ther., 17, 555-563.

12. Gram LF, Fredricson, Overr K (1975) First-pass metabolism of nortriptyline in man. Clin.

Pharmacol. Ther., 18, 305-314.

13. Boyes RN, Scott DB, Jebson PH, Godman MJ, Julian DG (1971) Pharmacokinetics of lidocaine

in man. Clin. Pharmacol. Ther., 12, 105-116.

14. Moore RG, Thomas J, Triggs EJ, Thomas DB, Burnard ED, Shanks CA (1978) The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. III. Mepivacaine. Eur. J. Clin.

Pharmacol., 14, 203-212.

15. Wolen RL, Gruber Jr CM, Kiplinger GF, Scholz NE (1971) Concentration of propoxyphene in

human plasma following oral, intramuscular, and intravenous administration. Toxicol. Appl.

Pharmacol., 19, 480--492.

16. Reinicke C, Rogner G, Franzel J (1970) Die Wirkung von Phenylbutazon und Phenobarbital auf

die Amidopyrin-Elimination, die Bilirubin-Gesamt-konzentration im Serum und einige blutgerinnungsfaktoren bei neugeborenen Kindem. Pharmacol. Clin., 2, 167-172.

17. Krauer B, Draffan GH, Williams FM, Clare RA, Dollery CT, Hawkins DF (1973) Elimination

kinetics of amobarbital in mothers and their newborn infants. Clin. Pharmacol. Ther., 14, 442447.

18. Caldwell J, Mofatt JR, Smith RL (1976) Pharmacokinetics of bupivacaine administered

epidurally during childbirth. Br. J. Clin. Pharmacol., 3, 956-957.

19. Aranda JV, Gorman W, Outerbridge EW (1977) Pharmacokinetic disposition of caffeine in premature neonates with apnea. Pediatr. Res., 11, 414.

20. Rane A, Bertilsson L, Palm6r L (1975) Disposition of placentally transferred carbamazepine

(Tegretol) in the newborn. Eur. J. Clin. Pharmacol., 8, 283-284.

21. Morselli PL, Principi N, Togoni G, Reali E, Belvedere G, Standen SM, Sereni F (1973) Diazepam elimination in premature and full-term infants and children. J. Perinat. Med., 1, 133-141.

22. Traeger A, Ntischel H, Zaumseil J (1973) Zur Pharmakokintic von Indomethazin bei

Schwangeren, Kreissenden und deren Neugeborenen. Zentralbl. Gyndikol., 95, 635-641.

23. Sj6qvist F, Bergfors PG, Borgh O, Lind M, Ygge H (1972) Plasma disappearance of nortriptyline

in a newborn following placental transfer from an intoxicated mother: evidence for drug metabolism. J. Pediatr., 80, 496-500.

24. Caldwell J, Wakile LA, Notarianni LJ (1978) Transplacental passage and neonatal elimination of

pethidine given to mothers in childbirth. Br. J. Pharmacol. (Abstr. Proc. B.P.S., Sept. 1977),

716P.

64



Determinants of drug disposition in infants

25. Gladtke E (1968) Pharmacokinetic studies on phenylbutazone in children. Farmaco Ed. Sci., 23,

897-906.

26. Rane A, Garle M, Borgh O, Sj/Sqvist F (1974) Plasma disappearance of transplacentally transferred phenytoin in the newborn studied with mass fragmentography. Clin. Pharmacol. Ther., 15,

39-45.

27. Aranda JV, Sitar DS, Parsons DW (1976) Pharmacokinetic aspects of theophylline in premature

newborns. N. Engl. J. Med., 295, 413-4 16.

28. Nitowsky HM, Matz L, Berzofsky JA (1966) Studies on oxidative drug metabolism in the fullterm newborn infant. Pediatr. Pharmacol. Ther., 69, 1139-1149.

29. Svensmark O, Buchtal E (1964) Diphenylhydantoin and phenobarbital. Serum levels in children.

Am. J. Dis. Child., 108, 82-87.

30. Jailing B, Bor6us LO, Rane A, Sj/Sqvist F (1970) Plasma concentrations of diphenylhydantoin in

young infants. Pharmacol. Clin., 2, 200-202.

31. Loughnan PM, Waters G, Aranda JV, Neims AH (1976) Age-related changes in pharmacokinetics of diphenylhydantoin (DPH) in the newborn and young infant: implications regarding treatment of neonatal convulsions. Austr. Paediatr. J., 12, 204-205.

32. Wilson JT, Atwood GF, Shand DG (1976) Disposition of propoxyphene and propranolol in children. Clin. Pharmacol. Ther., 19, 264-270.

33. Tomson G, Sundwall A, Lunell NO, Rane A (1979) Transplacental passage and kinetics in the

mother and newborn of oxazepam given during labour. Clin. Pharmacol. Ther., 25, 7481.

34. Gladtke E, Rind H (1967) Bilirubinstoffwechsel beim Neugeborenen. Monatsschr. Kinderheilkd.,

115, 231-233.

35. Vest MF, Rossier R (1963) Detoxification in the newborn. The ability of the newborn infant to

form conjugates with glucuronic acid, glycine, acetate and glutathione. Ann. N. Y. Acad. Sci.,

111, 183-197.

36. Wichmann HM, Rind H, Gladtke E (1968) Die Elimination von Bromsulphalein beim Kind. Z.

Kinderheilkd., 103, 262-276.

37. Rane A (1992) Drug disposition and action in infants and children. In: Yaffe SJ, Aranda JV (Eds)

Pediatric Pharmacology. Therapeutic Principles in Practice, pp 10-21. WB Saunders, Philadelphia, PA.

38. Ehrnebo M, Agurell S, Jailing B (1971) Age differences in drug binding by plasma proteins:

studies on human fetuses, neonates and adults. Eur. J. Clin. Pharmacol., 3, 189-193.

40. Krasner J, Yaffe SJ (1975) Drug protein binding in the neonate. In: Morselli P, Garattini S, Sereni F (Eds) Basic and Therapeutic Aspects of Perinatal Pharmacology, pp 357-366. Raven

Press, New York.

40. Sereni F, Perletti L, Marubini E, Mars G (1968) Pharmacokinetic studies with a long-acting sulfonamide in subjects of different ages. Pediatr. Res., 2, 29-37.

41. Chignell CF, Vesell ES, Starkweather DK et al (1971) The binding of sulfaphenazole to fetalneonatal and adult human plasma albumin. Clin. Pharmacol. Ther., 12, 897-901.

42. Ganshorn A, Kurz H (1968) Unterschiede zwischen der Proteinbindung Neugeborener und Erwachsener und ihre Bedeuting f~ir die parmakologische Wirkung. Arch. Pharm. Exp. Pathol.,

260, 117.

43. Kim PW, Krasula RW, Soyka LF, Hastreiter AR (1975) Postmortem tissue digoxin concentrations in infants and children. Circulation, 52, 1128-1131.

44. Kanto J, Errkola R, Sellman R (1974) Perinatal metabolism of diazepam. Br. Med. J., 1, 641642.

45. Pruitt AW, Dayton PG (1972) A comparison of the binding of drugs to adult and cord plasma.

Eur. J. Clin. Pharmacol., 4, 59-62.

65



Determinants of drug disposition in infants

46. Rane A, Lunde PKM, Jailing B, Yaffe SJ, Sj6qvist F (1971) Plasma protein binding of diphenylhydantoin in normal and hyperbilirubinemic infants. J. Pediatr., 78, 877-882.

47. Krasner J, Giaccoia GP, Yaffe SJ (1973) Drug protein binding in the newborn infant. Ann. N. Y.

Acad. Sci., 226, 101-114.

48. Tucker GT, Boyes RN, Bridenbaugh PO (1970) Binding of anilide-type local anesthetics in human plasma. II. Implications in vivo, with special reference to transplacental distribution. Anesthesiology, 33, 304-314.

49. Bor6us LO, Jalling B, Kfillberg N (1975) Clinical pharmacology of phenobarbital in the neonatal

period. In: Morselli P, Garattini S, Sereni F, (Eds) Basic and Therapeutic Aspects of the Perinatal

Pharmacology, pp 331-340. Raven Press, New York.

50. Short CR, Sexton RL, McFarland I (1975) Binding of 14C-salicylic acid and 14C-phenobarbital to

plasma proteins of several species during the perinatal period. Biol. Neonate, 26, 58-66.

51. Pacifici GM, Taddeucci-Brunelli G, Rane A (1984) Clonazepam serum protein binding during

development. Clin. Pharmacol. Ther., 35, 354-359.

52. Fredholm BB, Rane A, Persson B (1975) Diphenylhydantoin binding to proteins in plasma and

its dependence on free fatty acid and bilirubin concentration in dogs and newborn infants. Pediatr. Res., 9, 26-30.

53. West JR, Smith HW, Chasis H (1948) Glomerular filtration rate, effective renal blood flow and

maximal tubular excretory capacity in infants. J. Pediatr., 32, 10-18.

54. Barnett HL, McNamara H, Schultz S, Tompsett R (1949) Renal clearances of sodium penicillin

G, procaine penicillin G and insulin in infants and children. Pediatrics, 3, 418-422.

55. Rane A, Wilson JT (1976) Clinical pharmacokinetics in infants and children. Clin. Pharmacokinet., 1, 2-24.



66



Drugs and Human Lactation

P.N. Bennett, editor

9 Elsevier Science Publishers B.V., 1996



5. Use of the monographs on drugs



PRESENTATION OF DATA

Drugs in this text are named according to their entries in the Cumulative List No. 8

of the International Nonproprietary Names (INN) for Pharmaceutical Substances

published by the World Health Organization, Geneva, 1992. Other commonly-used

names are included in the general description of a drug; these are referenced in the

index to help the reader who is not familiar with the INN usage.

Clearly there is variation in the drugs contained in the pharmacopoeias of different countries and readers may be unfamiliar with, or even surprised to see, certain

drugs in this book. The INN also lists the names of drugs from various national

pharmacopoeias. Such listing has been taken to mean that a drug is currently in use,

and thus it has been included in this book.

The text provided on each drug opens with a general section, considering briefly

the clinical use of the drug, and its simple pharmacokinetics. The quoted pharmacokinetic values are taken from various standard sources and are not referenced

individually. In the second section a table usually follows in which the essential

data are presented. The table looks like this:

Treatment conditions

Dose • Frequency •

Duration; Route; No.

of patients; Lactation

stage



Concentration

(mg/1)

Milk



Milk/

plasma

ratio

Plasma



Maximum

observed

milk conc.

(mg/l)



Absolute dose

to infant (mg/kg day)

Ave



Ref.



Max



Treatment conditions

The treatment conditions can include a number of regimens and are represented as"

Dose x Frequency x Duration (e.g. 100 mg x 3/d x 14 d);

Route; Number of patients; Lactation stage.

67



Use of the monographs on drugs



The dose is usually specified in milligrams (mg); in this case 100 mg. The frequency in this example is shown by, e.g. x 3/d, which indicates 3 doses daily. The

duration is shown by, e.g. x 14 d, which indicates 14 days. (A single dose is shown

as x 1/d x 1 d.). The route is shown as p.o., i.v., i.m. etc. The number of subjects

is shown as, e.g. n = 6 or n = 10, indicating that 6 or 10 subjects were studied. The

lactation stage is often shown by a question mark which implies that the stage of

lactation is unknown (many studies examined). It is presumed that this indicates

established lactation. In some cases colostrum or transitional milk was examined.



Concentrations

The concentration of drug in milk or plasma is shown as mg/1 in most cases

(occasionally/tg/1 or ng/1). A figure of <50/zg/1 indicates that the drug was not detectable at the sensitivity level of the assay (in this case 50/tg/1). If the assay sensitivity is not known the abbreviation n.d. (for not detected) is used. A figure in parentheses indicates a concentration of metabolite.



Milk to plasma ratio

The milk to plasma ratio (M/P) is calculated for paired samples or from the areas

under the respective concentration-time curves; in some cases a range is given

which reflects intersubject variation.



Dose

The assumption is made that the infant ingests milk at the rate of 150 ml/kg day.

The average dose is then calculated from the data shown in column 2 and expressed

as mg or mg/kg per day. The maximum dose is calculated from the maximum milk

concentration. The relative dose to the infant is then given both in terms of the maternal dose and of the paediatric therapeutic dose where this is available (see assumptions on page 70).

There follow comments on any observed effects or drug measurements in the infants. The section on each drug finishes with an assessment and recommendations,

and with references. The criteria used for the general recommendations are shown

in the discussion on assumptions on pages 69-74.

SELECTION AND REJECTION OF EVIDENCE

Readers may notice that certain references are missing from this book, and indeed

information on some drugs has been excluded altogether. In some cases no data

were available, and in other cases the data were inconclusive. Many of the early

studies in this field used spectrophotometric or colorimetric methods, or measured

68



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