ADDRESS FOR REPRINTS: Montreal Children’s Hospital, 2300 Tupper Street, Montreal 108, Canada.
PsniAnucs, Vol. 49, No. 8, June 1972
PHARMACOLOGY
FOR
THE
PEDIATRICIAN
DRUG
INTERACTIONS-PART
II
Drugs,
the
Newborn
Infant,
and
the
Binding
of
Bilirubin
to Albumin
Leo Stern, M.D.
Director, Department of Newborn Medicine, Montreal Children’s Hospital; Associate Professor of Pediatrics, McGill University
Unlike its conjugated (direct acting)
counter-part, unconjugated (indirect acting) bilirubin is insoluble in water, but highly soluble in lipids.
Hence, it tends to diffuse out of plasma into the
lipid-rich CNS with resultant kernicterus. This does not occur when unconjugated bilirubin is
bound to albumin, as the complex is too large
for diffusion. The production of kernicterus thus
involves the increase of free, unbound,
uncon-jugated bilirubin in plasma, either by
dissocia-tion from its albumin binding sites or by the
in-troduction of one or more anions which compete preferentially for a common or shared site, thus
displacing the bilinibin from its albumin bond.
- FACTORS AFFECTING BINDING
VLowering the pH promotes bilirubin-albumin dissociation,’ and acidosis has thus been impli-cated as a factor in kernicterus occurring at low levelsofrum bilirubin.25 In addition,
corn-petition for bilirubin binding sites is exhibited
by a number of endogenously occurring sub-stances as well as exogenously administered agents. Both hematin (increas in hemolytic
states) and t e
(in-creased under conditions of both h hermia6
and ypog ycemia7 are capa e of displacing biliru in om its albumin binding sites. In
ad-dition, a number of drugs, among which
sul-fisoxazole (Gantrisin)_is the most widely known
in view of lilIs clinical8 and experimental
production of kernicterus in this fashion, are capable of causing similar displacement in vitro.
Among the techniques employed to demon-strate an increase in free bilirubin is the mea-surement of displacement of spectral curves.10’7’ The technique depends on a difference in ab-sorbance of free (420 to 440 nm
)
versus bound(460 to 465 nm) bilirubin, with changes in the
shapes of the curves as the amounts of free and
bound bilirubin are altered. Quantitative de-termination of the amount of free bilirubin
re-suiting from a given competitive anion can be
obtained by Sephadex Gel fiitration.12,13 The
heavier, albumin-bound bilirubin goes through
the column more quickly than the lighter, free
portion. The latter, trapped in the Sephadex,
can then be measured directly.
In addition to sulfisoxazole, both s,Jjte
and are known to
dis-place bilirubin from albumin.b0,11 Recent studies
in our department have demonstrated a similar
uncoupling capacity for both
Orinase_(tolbuta-mide) and the
(diazepam) . Several other agents (see Table I)
show similar although quantitatively less in vitro activity.
Clinically, assessing the significance of these
in vitro findings requires taking account of
several factors. The in vitro conditions used
represent a highly unusual bilirubin-albumin
relationship (excessive bilirubin and reduced
albumin) . Nevertheless, displacement of the
order of magnitude obtained in the laboratory
has resulted in clinical kernicterus with at least one of the agents shown in the Table
(Gan-trisin
)
.Recent evidence suggests that different anions
may compete either totally or partially with
bilirubin for albumin binding. Thus, the bind-ing of nonesterified fatty acids to albumin prob-ably involves three sites, of which only one is shared with bilirubin. It is only after the first two have been occupied that any displacement of bilirubin occurs?3 The clinical risk of free bilirubin from any drug is dependent on the
drug concentration itself, whether it is totally
or partially competitive for binding, the in vivo
bilirubin/albumin ratio, the simultaneous
exist-ence of other local conditions (i.e., acidosis,
by-pothermia) , and the presence or absence of
other competitive anions.
For the physician administering drugs to
new-born infants. The temptation to try a new agent with a slightly different structure (common
PHARMACOLOGY FOR THE PEDIATRICIAN 917
TABLE I
I)ituos CAPABLE OF IN Vimo DISPLACEMENT OF
BILIRuBIN FROM ALBUMIN ON SEPLIADEX
G-5 COLUMNS
Caffeine Sodium Benzoate
Sodium Salicylate l)iazepam (Valium)* Tolbutamide (Orinase) Sulfisoxazole (Gantrisin)
Furosemide (Lasix) Sodium Oxacillin (Prostaphlin) Hydrocortisone
Gentamycin (Geramycin) Digoxin
Sodium Meralluride (Mercuhydrin)
Sulfadiazine
(Generic and trade names are listed in order of quantitative displacement exhibited; concentrations of
drugs used were those of in vivo levels resulting from manufacturers’ recommended dosages.)
* Injectable preparation only.
l)ata from Chan, G. : The Binding of Bilirubin to Albumin, M.Sc. Thesis, Department of Experimental Medicine, McGill University, 1971.
a guarantee of similar bindings characteristics
(viz., salicylate displaces; salicylamide does not). Similarly, oxacillin dis laces, but methicillin and penicillin#{231}iot. Any drug used in the new-born must have, in addition to its other
meta-bolic and pharmacokinetic data, some form of
\
study to determine its capacity to displacebili-\rubin from albumin.
Drugs may reach the newborn not only
di-rectly, but also via breast milk of a nursing mother, as well ascordjJooLif adminis-tered just prio to or during labor (e.g.jsycho-tropic, sedative, and tranquilizing agentij At present, neither The Food and Drug Adminis-tration nor its Canadian counterpart, the Food and Drug Directorate, requires information on
alb,imi’iJilirubin displacement from the
manu-facturer for licensing a drug. The information is not difficult to obtain and should be made
man-datory for every drug, irrespective of whether the manufacturer intends it to be used for
new-born infants or not.
Recent findings with respect to caffeine
so-dium benzoate (see Table I) emphasize the
prob-lem of different formulations of the same
com-pound. Studies by Schiff, et al.’ have shown
that the bilirubin-albumin displacement effect
of this agent stems from the sodium benzoate
portion, the active principle, caffeine, being free
of any competitive effect. Sodium benzoate is
a frequently used preservative and stabilizer
for injectable preparations. This study further demonstrated that the displacement effect of
Valium Injectable is due not to the therapeutic
agent (diazepam) but to the sodium benzoate
present in the vehicle. Therefore, not only do
such studies need to be made for related drugs and compounds, but the information is
manda-tory for any formulary change in the drug itself.
REFERENCES
1. Odell, C. B., and Cohen, S.: The effect of pH on the binding of bilirubin. Amer. J. Dis. Child., 105:525, 1960.
2. Stem, L., and Denton, R. L. : Kemicterus in
small premature infants. PEDIATRICS, 35:483, 1965.
3. Stem, L., and Doray, B.: Hypothermia,
acido-sis and kernicterus in small premature
in-fants. Proc. XIIth Int. Cong. Pediat., Mexico, D.F., pp. 512-513, 1968.
4. Ackerman, B. D., Dyer, C. Y., and Leydorf,
M. : Hyperbilirubinemia and kernicterus in
small premature infants. PEDIATRICS, 45:917, 1970.
5. Gartner, L. M., Snyder, R. N., Chalon, R. S.,
and Bernstein, J.: Kernicterus : High mci-dence in premature infants with low serum
bilirubin concentration. PEDIATRICS. 45:906. 1970.
6. Schiff, D., Stem, L., and Leduc, J.: Chemical thermogenesis in newborn infants :
Catechol-amine excretion and the plasma non-esteri-fled fatty acid response to cold exposure.
PE-DIATRICS, 37:577, 1966.
7. Dole, V. P. : A relation between non-esterified
fatty acids in plasma and the metabolism of glucose. J. Clin. Invest., 35:50, 1957. 8. Silverman, W. A., Anderson, D. H., Blanc,
w. A., and Crozier, D. N. : A difference in mortality rate and incidence of kernicterus among premature infants allotted to two
prophylactic antibacterial regimes. PEDIAT-RICS, 18:614, 1956.
9. Johnson, L., Sarmiento, F., Blanc, W. A., and Day, R. L.: Kernicterus in rats with
inher-ited deficiency in glucuronyl transferase.
Amer.
J.
Dis. Child., 97:591, 1959.10. Odell, G. B. : The dissociation of bilirubin from
albumin and its clinical implications. J.
Pe-diat., 55:268, 1959.
11. Khanna, N. R., Harpur, E. R., and Stem, L.:
In vitro effect of sodium phenobarbital and
AMERICAN
ACADEMY
OF
PEDIATRICS
COMMITTEE ON ENVIRONMENTAL HAZARDS
LEAD
CONTENT
OF
PAINT
APPLIED
TO
SURFACES
ACCESSIBLE
TO
YOUNG
CHILDREN
918 DRUG INTERACTION-PART II
PEDIATRICS, Vol, 49, No. 6, June 1972
12. Kaufman, N. A., Kapitulnik, M. S., and
Blond-helm, S. H. : The adsorption of bilirubin by Sephadex and its relationship to the criteria for exchange transfusion. PEDIATRICS, 44:
543, 1969.
13. Chan, C., Schiff, D., and Stem, L.:
Competi-live binding of free fatty acids and bilirubin to albumin. Differences in HBABA dye vs.
Sephadex G-25, interpretation of results.
Clin. Biochem., 4:208, 1971.
T
HE Committee on Environmental Haz-ards has recommended that the Amen-can National Standards Institute (ANSI)revise that portion of the American
Stan-dard Z66.1/64 pertaining to the lead
con-tent of paint downward from the present
1% to “minimum traces” or <0.06% of the total weight of the contained solid,
includ-ing pigment, film solids, and driers. This
recommendation is based on a study of
re-cently published materia1s’ which ap-peared after the 1% voluntary standard for lead was originally established in 1955 by ANSI.
At the same time, in response to the no-tice in the Federal Register of November 2,
1971 (21 CFR Part 191
),
the Committee recommended that Federal standards for lead content of paint used on surfacesac-0 This DPI is concerned primarily with
mere-ments in oral intake of inorganic lead salts. In
calculating this DPI, it was assumed that average daily respiratory exposure in most urban areas is
approximately 2 tg Pb/rn’. Any significant
in-crease in respiratory intake would have to be given added weight because respiratory retention is
esti-mated at 35 to 40% of very small lead-bearing par-ticulates in the lower respiratory tract.
Assimila-tion in the gastrointestinal tract is estimated at
5 to 10% of oral intake. It is understood that the
comments in this statement apply almost exclu-sively to increments in oral intake in the presence
of constant but low levels of respiratory exposure (2 g Pb/rn’ on the average).
14. Schiff, D., Uian, G., and Stern, L.: Fixed drug combinations and the displacement of
biliru-bin from albumin. PEDIATRICS, 48:139, 1971.
Contributions to “Pharmacology for the
Pedi-a:trician” and comments should be addressed to
Dr. Charles F. Weiss, Department of Pediatrics,
Urdvei*y Hospital, Box 739, Gainesville,
Florida 32601.
cessible to young children be reduced to
“minimum traces” on <0.06%, and that
paints containing more than this amount of lead be banned as hazardous substances.
On review and evaluation of available data in children and adults, an ad hoc
corn-mittee (B. C. King, Chairman)’ recently
concluded that, for children, the maximum daily permissible intake
(
DPI)
of lead from all sources should not exceed 300 tg Pb/day.#{176} If average daily intake is main-tamed below this level, blood lead concen-trations are unlikely to exceed 40 pg Pb/ 100 gm whole blood. At this level of in-take, it is estimated that the amountas-siinilated by 1- to 3-year-old children could probably be excreted so no net increment in total body lead burden would be antici-pated. It is estimated that approximately one half of this 300 g Pb/day intake would be derived from usual food, water, and air, so intake from all other sources, on the
average, should not exceed 150 &g Pb/day. In particular, average daily intakes below this DPI would not be associated with any significant increment in soft tissue lead con-tent. It is this portion of the total body lead burden which appears to be responsi-ble for the known toxic effects of lead.
Available data indicate that increments
