plasma creatinine. Clin Chem 1981;27:1953-4.
7. Saah AJ, Koch TR, Drusano GL. Cefoxitin falsely elevates
creatinine levels. JAMA 1982;247:205-6.
8. Henry RJ. Clinical chemistry: principles and technics. New
York: Hoeber, 1964:287.
9. Neu HC, Srinivasan S. Pharmacology of ceftizoxime compared
with that of cefamandole. Antimicrob Agents Chemother
1981;21:366-9.
10. Stoeckel K. Pharmacokinetics of Rocephin, a highly active new
cephalosporin with an exceptionally long biological half-life. Chemo-
therapy 1981;27(suppl 1):42-6.
II. Harding SM, Monro AJ, Thornton JE, et al. The comparative
pharmacokinetics of ceftazidime and cefotaxime in healthy volunteers.
J Antimicrob Chemother 1981;8(suppl B):263-72.
12. Brogden RN, Carmine A, Heel RC, et al. Cefoperazone: a
review of its in vitro antimicrobial activity, pharmacological prop-
erties and therapeutic efficacy. Drugs 1981;22:423-60.
13. Swabb EA, Leitz MA, Pilkiewicz FG, et al. Pharmacokinetics
of the monobactam SQ 26,776 after single intravenous doses in healthy
LETTERS
••••••••••••
Naproxen Excretion in Milk and its Uptake by the Infant
TO THE EDITOR: The possible presence of drugs in breast milk fre-
quently prompts questions by nursing mothers concerned about the
safety of the suckling infant when the mother is under drug therapy.
This information is crucial particularly when a mother is suffering
from a chronic disease, such as rheumatoid arthritis. Naproxen is an
antiinflammatory acid commonly used in the treatment of rheumatoid
arthritis. It elicits its therapeutic effects after daily administration of
500-3000 mg, with infrequent significant side effects. I However, no
information as to the disposition of naproxen in breast milk and its
uptake by the infant is available. We have investigated naproxen mam-
mary excretion in a nursing mother and the uptake of the drug by
the suckling infant.
A nursing mother with rheumatoid arthritis was referred to us for
measurement of naproxen in her breast milk. She was 23-years-old,
weighed 59 kg, and had been under therapy with naproxen (Naprosyn,
Syntex, Inc.) 250 mg bid for eight months. The infant, a healthy
5-month-old, 8-kg boy, was breast fed regularly. The purpose of the
drug analysis was to investigate the amount of naproxen in the milk
and the feasibility of increasing the mother's dose to 375 mg bid
without exposing the infant to large quantities of the drug through
feeding. The mother was taking no other medication.
To ascertain the attainment of the steady-state drug level, urine and
milk samples were collected over two consecutive periods of dosing
intervals. Following ingestion of the first routine daily 250-mg dose,
milk (5-10 ml) and urine (total output) were collected from the mother
at 0,2,4,8, and 12 h, and during the second daily dose interval at 4,8,
and 12 h postdosing. After analysis of the drug in the specimens, the
dosage regimen was increased to 375 mg bid and, three weeks later,
milk and urine samples were taken from the mother at 0,2,4, and
12 h following the first daily dose. Using disposable plastic bags, urine
(total output) of the infant also was collected during the same dosing
interval at 0, 2.8, 5, 10, and 12 h. The infant went to the breast at
1.2 and 5.5 h postdosing. Naproxen concentrations in milk and urine
(after alkaline hydrolysis of conjugates) were determined, using the
high performance liquid chromatography method of Upton et al.'
Regression lines passing through the declining terminal phase of
the mother's urinary excretion rate curves (Figure 1) indicate half-
lives (tYz) of 8.75 hand 7.75 h for the first and second daily doses,
respectively, of 250 mg. This value was 8.50 h for the 375-mg dose
curve. Total cumulative urinary excretions (EXu) of naproxen after
910 Drug Intelligence and Clinical Pharmacy
Downloaded from aop.sagepub.com at DALHOUSIE UNIV on June 4, 2016
subjects. J Antimicrob Chemother 1981;8(suppl E):131-40.
14. Foord RN. Cephaloridine and the kidney. In: Progress in anti-
microbial and anticancer chemotherapy: proceedings of the 6th Inter-
national Congress of Chemotherapy. Vol I. Tokyo: University of
Tokyo Press, 1970:597-604.
15. McKendrick MW, Legg EF. In vivo and in vitro interference
due to cefotaxime on the assay of creatinine. J Clin Pathol
1981;34:224-5.
16. Kroll M, Koch T, Drusano GL, et al. Moxalactam, cefotax-
ime, cefoperazone and ceftazidime do not interfere with creatinine
determinations in serum or urine. 22nd Interscience Conference on
Antimicrobial Agents and Chemotherapy, Oct 4-6, 1982, Miami Beach
(abstract 525).
17. Guay DRP, Meatherall RC, Macaulay PA. Interference of
selected second- and third-generation cephalosporins with creatinine
determination. Am J Hosp Pharm 1983;40:435-8.
18. Polk RE, Stephens GH. Effects of cefazolin and moxalactam
on serum chemistry values determined by autoanalyzer. Am J Hosp
Pharm 1981;38:866-8.
alkaline hydrolysis were 100.6 and 120.6 mg for the first and second
250-mg doses, which constitute 40.3 percent and 48.2 percent of the
administered dose, respectively. The observed EXu following inges-
tion of the 375-mg dose was 179.4 mg, or 47.8 percent of the dose.
These EXu values agree with the 43-65 percent reported by others!
Maximum milk naproxen concentrations appeared four hours postdos-
ing and were 0.125 mg 0J0 and 0.114 mgOJo; lines through the terminal
points had half-lives of 22.8 hand 23.8 h after administration of the
first and second 250-mg doses, respectively (Figure I). The peak mam-
mary concentration after the 375-mg dose was 0.237 mgOJo. Breast
milk pH ranged from 6.5-6.8 throughout the experiment.
The infant excreted 0.47 mg total intact and conjugated naproxen
during the mother's 375-mg dosing interval (Figure 2). This consti-
tutes 0.26 percent of the EXu observed in the mother. Assuming that
a 5-month-old infant exhibits the same pattern of naproxen metab-
olism as an adult, the ratio of EXu of the infant over that of the mother
provides a measure of the ingested dose of the drug by the infant.
Only 0.26 percent of the mother's dose was recovered from the infant.
,)
~
s
~lO
~
•
• •
•
•
•
•
•
i • •
" 5
O,l)-
\10.20
o
.:':0.10
•~
iii
~O.(E
10 15 20 25 10
fbco,
Figure 1. Steady-state urinary excretion rate of naproxen after alkaline hydrolysis
and corresponding milk naproxen concentrations during oral administration of 250
rng bid ( . ,0) and 375 mg bid (_,0), respectively. to a nursing mother.
VOL17 DEC 83
 0.5
6
f1,,,,,
10 12
Figure 2. Cumulative urinary excretion of naproxen after alkaline hydrolysis in an
infant nursed regularly by his mother who was ingesting naproxen 375 mg bid.
Very low milk naproxen concentrations are consistent with this
observation. Other acidic drugs such as salicylate," ibuprofen,' and
flufenamic acid" also have limited mammary excretion, due, perhaps,
to the more acidic nature of milk as compared with plasma.' To draw
a definite conclusion as to the safety of naproxen therapy during
different stages of lactating period, more subjects must be examined.
Nevertheless, based on these observations, one may conclude that the
extent of naproxen ingestion from breast milk of mothers under
chronic therapy with this drug is limited and unlikely to cause signifi-
cant consequences in the suckling infant.
FAKHREDDIN JAMALI, Ph.D.
Assistant Professor of Pharmacokinetics
DOUGLAS R.S. STEVENS
Pharmacy Student
Faculty of Pharmacy and Pharmaceutical Sciences
The University of Alberta
Edmonton, Alberta T6G 2N8, Canada
References
1. Day RO, Furst DE, Dromgoole SH, Kamm B, Roe R, Paulus
HE. Relationship of serum naproxen concentration to efficacy in
rheumatoid arthritis. Clin Pharmacol Ther 1982;31:733-40.
2. Upton RA, Buskin IN, Guentert TW, Williams RL, Riegelman
S. Convenient and sensitive high-performance liquid chromatography
assay for ketoprofen, naproxen and other allied drugs in plasma or
urine. J Chromatogr 1980;190:119-28.
3. Segre EJ. Naproxen metabolism in man. J Clin Pharmacol
1975;15:316-23.
4. Jamali F, Keshavarz E. Salicylate excretion in breast milk. Int
J Pharm 1981;8:285,290.
5. Weibert RT, Townsend RJ, Kaiser DG, Naylor AJ. Lack of
ibuprofen secretion into human milk. Clin Pharm 1982;1:457-8.
6. Buchanan RA, Eaton CJ, Koeff ST, Kinkel AW. The breast
milk excretion of flufenamic acid. CUff Ther Res 1969;1l:533-8.
7. Rasmussen F. Mammary excretion of sulphonamides. Acta
Pharmacol ToxicoI1958;15:139-48.
Comments and Corrections on Dosing Guidelines
TOTHEEDITOR: In the article entitled "Gentamicin and Tobramycin
Dosing Guidelines: An Evaluation" (DICP 1983;17:425-32), the
authors present guidelines that they have developed to standardize
their pharmacokinetic dosing service in which a number of pharmacists
participate. These guidelines are expected to promote consistent inter-
pretation and application of clinical and kirietic data.
Some readers may attempt to adopt these guidelines for applica-
tion in their institutions. However, they should be cautioned to apply
the intermittent infusion equations in this article carefully (Eq. I,
Appendix Eq. 7 and 8). These equations assume the duration of amino-
glycoside infusion to be one hour. However, in many institutions,
the duration of infusion often varies, from 15 to 60 minutes. In this
situation, if the maintenance dose (administered in < 60 min) is in-
corporated into Equation 1 without conversion to mg/h, CPmax will
be underestimated.
This potential error can be prevented by rewriting Equation 1 in
the article as follows:
K o.(I- e- Kelt)
CPmax= K corrected as follows:
KelYd (l-e- elT)
where K o is the zero-order infusion rate in mg/h; K o can be deter-
Drug Intelligence and Clinical Pharmacy VOL 17
Downloaded from aop.sagepub.com at DALHOUSIE UNIV on June 4, 2016
mined by dividing the MD (maintenance dose) by the duration of
. fusi
In usion (K0 = MD
-t-)'
Sawchuk and Zaske originally described this equation using the term
K O • 1 The use of K o in describing the dose administered also should
be considered when using the Appendix Equations 7 and 8 of this
article.
The authors also provide guidelines for establishing a dosing regimen
in patients receiving hemodialysis and peritoneal dialysis. They describe
a method of predicting the K el of these patients. However, no men-
tion is made of the in vivo inactivation of aminoglycosides by
penicillins and semisynthetic penicillins. This can shorten the amino-
glycoside half-life significantly in patients with severe renal
insufficiency.i' This factor should be taken into account in dosing
renal-failure patients when penicillins or semisynthetic penicillins are
added to or deleted from the dosing regimen.'
DIANE E. BECK, Pharm.D.
Assistant Professor
Department of Clinical Pharmacy Practice
School of Pharmacy
Auburn University
Auburn University, Alabama 36849
References
1. Sawchuk RJ, Zaske DE. Pharmacokinetics of dosing regimens
which utilize multiple intravenous infusions: gentamicin in burn pa-
tients. J Pharmacokinet Biopharm 1976;4: 183-95.
2. Kradjan WA, Burger R. In vivo inactivation of gentamicin by
carbenicillin and ticarcillin. Arch Intern Med 1980;1l0:1668-70.
3. Russo ME, Thor EA. Gentamicin and ticarcillin in subjects with
end-stage renal disease. Comparison of two assay methods and evalua-
tion of inactivation rate. Clin NephroI1981;15:175-80.
4. Chow MS, Quintiliani R, Nightingale CH. In vivo inactiva-
tion of tobramycin by ticarcillin-a case report. JAMA
1982;247:658-9.
TOTHEEDITOR: Clarification should be made in the use of equations
that appeared in the article "Gentamicin and Tobramycin Dosing
Guidelines: An Evaluation." Equation I, on page 427, defines the
steady-state peak (CPmax) as follows:
MD (l-e-Kel t)
YdK d • (l-e- K elT)
The term K d is, of course, supposed to be K el . However, of greater
importance is the missing infusion time (t) factor in the denominator.
Equation 1 should be written as:
MD • (l-e- K elt )
CPmax = -Y--=-d"'K=-e-It- (1 - e - KelT)
Some authors define maintenancedose as dosage (mg)/infusion time
(h). However, it is clear from the use of the equation on page 430
(Eq, 7) that MD is intended to be a dosage in milligrams, rather than
a dosage rate.
Infusion time (t) should be added to Equation I and subsequent
equations, to prevent major errors in maintenance dose and concen-
tration calculations.
PHILLIP HANN, Pharm.D.
Director
Education and Professional Services
AMI Pharmacy Management Services
Encino, California 91436
NOTE: This same error was brought to our attention by L.J. Coglan,
pharmacist, Mesa Lutheran Hospital, Mesa, AZ.-ED.
AUTHOR'S REPL v: It has been brought to my attention that there are
two errors in our article "Gentamicin and Tobramycin Dosing Guide-
lines: An Evaluation." The errors are on page 431 and involve Equa-
tions 11 and 12. The errors in the mathematical statement should be
_ dose
Yd- Eq. 11
KelPt
DEC 83 911