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Docetaxel Secretion in Tears
Association With Lacrimal Drainage Obstruction
Bita Esmaeli, MD;
M. Amir Ahmadi, MD;
Edgardo Rivera, MD;
Vicente Valero, MD;
Toni Hutto, BS;
Denise M. Jackson, RN;
Robert A. Newman, PhD
Arch Ophthalmol. 2002;120:1180-1182.
ABSTRACT
Objective To test the hypothesis that docetaxel may be secreted in tears after
intravenous infusion.
Design Prospective pilot trial.
Patients and Methods Tear fluid was collected from 4 patients receiving docetaxel weekly
and 2 patients receiving docetaxel every 3 weeks as a single agent for the
treatment of metastatic breast cancer. Tear samples were collected once prior
to and again within 30 minutes following the end of the 1-hour docetaxel infusion.
A blood sample was also obtained after infusion. The tear and plasma samples
were analyzed for drug content using high-performance liquid chromatography
and tandem mass spectrometry.
Results Docetaxel was found in the tear samples collected from all 6 patients.
Conclusion The secretion of docetaxel in tears may be a mechanism for canalicular
inflammation and tear drainage obstruction, which are known to occur as an
adverse effect of the drug.
INTRODUCTION
DOCETAXEL (Taxotere; Aventis, Bridgewater, NJ) is an effective antineoplastic
agent that is widely used for the treatment of metastatic or locally advanced
breast cancer.1-2 We have previously
reported that stenosis of the canaliculi and blockage of the nasolacrimal
ducts are common adverse effects of the weekly administration of docetaxel.3-5 In this study, we sought
to test the hypothesis that docetaxel may be secreted in tears. The secretion
of docetaxel in tears would suggest that closure of the lacrimal drainage
apparatus may be due in part to its direct contact with the drug.
PATIENTS AND METHODS
Four patients receiving docetaxel once a week and 2 patients receiving
docetaxel once every 3 weeks as a single agent for the treatment of metastatic
breast cancer were enrolled in our study between October 2001 and January
2002. To be eligible for inclusion in the study, patients could not have received
docetaxel for at least 6 weeks before enrollment. Before the start of docetaxel
treatment, each patient underwent a baseline ophthalmologic examination, including
slitlamp biomicroscopy and in-office probing and irrigation, to ensure that
no abnormalities were present in the tear film, on the ocular surface, or
in the tear drainage apparatus. The protocol was approved by the institutional
review board. Informed consent was given by all patients enrolled in the study.
TEAR SAMPLE COLLECTION TIMES
Docetaxel was administered intravenously to each patient in 1-hour infusions.
During the first infusion of docetaxel, 2 samples of tear fluid were collected
from each patient: one sample immediately before infusion to serve as a baseline
or control sample, and another sample within 30 minutes after the end of infusion.
A 5-mL blood sample was also obtained within 30 minutes after the end of infusion.
TEAR SAMPLE COLLECTION METHOD
To anesthetize the conjunctival surface, a drop of topical proparacaine
hydrochloride was placed in each eye. Polyester rods (Filtrona Richmond, Inc,
Richmond, Va) were placed in the inferior lateral conjunctival fornix (Figure 1). For each sample, 2 polyester rods
were used (1 in each eyelid) to collect the volume of tears required for analysis.
During sampling, care was taken to avoid irritating the ocular surface and
eyelid margin. No agent other than ambient light was used to stimulate tear
production. Collection time was limited to 1 to 2 minutes or until 50 µL
of tears was obtained, whichever occurred first. Tear collection was monitored
by direct visualization of the wetting of the rods' polyester substrate. After
sampling, the rods were suspended in a microcentrifuge tube that contained
a shortened micropipette tip and were frozen at -70°C. Tear fluid
was subsequently recovered using centrifugation at 13 200g at 4°C for 10 to 15 minutes. The volume collected from each rod
was measured; tear volumes typically ranged from 15 to 30 µL.
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Method of tear collection using a polyester rod placed in the inferior
lateral conjunctival fornix.
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ANALYSIS OF DRUG CONCENTRATIONS IN TEAR AND SERUM SAMPLES
Docetaxel concentrations in the tear and serum samples were determined
by direct injection of the tears or extracted plasma into a tandem mass spectrometer
(Ultima Quattro LC/MS/MS; Micromass, Beverly, Mass) equipped with a binary
high-performance liquid chromatography system (Agilent 1100; Agilent Technologies,
Wilmington, Del). Docetaxel was identified and quantified using negative-ion
electrospray mass spectrometry in multiple-reaction monitoring mode with the
transition ion (806.5>654.4 [mass/charge], or parent>major product). Chromatographic
conditions included a rapid methanol gradient (10mM ammonium acetate; pH level,
8.5) starting at 20% methanol and ending at 95% methanol within 5 minutes.
The flow rate was 250 µL/min, and the column temperature was 45°C.
The chromatographic separation of docetaxel from background noise was accomplished
using an analytical column (3 µm; 2 x 100 mm; Xterra C18; Waters,
Milford, Mass). The lower limit of quantitation for docetaxel in the tandem
mass spectrometer was 10 ng.
Docetaxel was measured in plasma using solid-phase extraction. After
the extraction cartridges (C2; Varian, Palo Alto, Calif) were prepared according
to the manufacturer's instructions, 1 mL of plasma was passed through them.
The cartridges were then washed with 2 mL of an 0.01M ammonium acetate solution
(pH level, 5.0) followed by 2 mL of a methanol/0.01M ammonium acetate buffer
(pH level, 5.0) in a 20:80 vol/vol mixture. The drug was eluted from the columns
with 300 µL of 100% methanol. A 25-µL aliquot of the resulting
extract was injected directly into the tandem mass spectrometer.
RESULTS
Table 1 shows the patient
characteristics, dose intensity of docetaxel, and concentrations of the drug
in tear and plasma samples collected after drug administration. Although docetaxel
was not present in any of the baseline (control) samples of tears, it was
found in the tear samples collected from all 6 patients after injection of
the drug. The concentrations of docetaxel were 1.4 to 7 times (mean, 4.5 times)
higher in plasma than in tears.
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Docetaxel Concentrations in Tears and Plasma
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COMMENT
The detection of docetaxel in tears collected from all 6 patients after
its injection supports our hypothesis that the ocular surface irritation and
fibrosis of the tear drainage ducts seen following treatment with this drug
may be partly due to direct contact between the drug and both the conjunctival
surface and mucosal lining of the tear drainage apparatus.
The concentrations of several drugs, including valproic acid, acetaminophen,
lithium, phenobarbital, carbamazepine, and methotrexate, have been previously
quantitated in tears.6-9
Transfer of the free non–protein-bound fraction from plasma to tears
can be expected only with drugs that are not ionized and that have sufficient
lipid solubility. Previous studies have demonstrated that concentrations of
drugs in tears are proportionate to the concentration of free drug in plasma.10-11 Tears seem to have a relatively constant
protein content (0.6-0.8 g/dL), and the passage of small molecules with low
binding properties to plasma proteins via secretion into the tears is fairly
unimpeded.12 Docetaxel is water insoluble and
seems to readily cross physiologic barriers. The drug strongly binds to plasma
proteins, with an in vitro plasma binding rate of of 93% to 94% regardless
of the drug concentration.13 In our study,
the concentration of docetaxel in the plasma of all 6 patients was several
times higher than the concentration of the drug in tears from these patients.
These findings suggest that only a small fraction of the administered dose
of docetaxel (ie, the unbound portion) has access to the tear film.
The method of tear collection in our study was simple and did not cause
ocular adverse effects. In most cases, ambient light was an adequate stimulus
for tear production. Previous studies have used several methods for the collection
of tear samples, including the use of glass micropipettes,14
Schirmer paper strips,15 and the polyester
rods16 used in our study. We prefer to use
polyester rods because they are easy to handle and do not seem to cause discomfort
to the patients.
Various alternative methods for the detection of drugs in tear samples
have also been proposed, including gas chromatography coupled with mass spectrometry15 and high-performance liquid chromatography.17 A high-performance liquid chromatograph in combination
with a tandem mass spectrometer permits the precise determination of compounds
through measurement of their exact molecular weight and through production
of a fragmentation pattern unique to the compound being analyzed. Detection
limits at the level of picograms or lower are possible. We chose our method
because it gives reproducible results and because a volume of tears as small
as 50 µL was adequate for the detection and quantitation of docetaxel.
The aim of our study was to determine whether docetaxel is secreted
in tears. We did not attempt to examine the pharmacokinetics of drug secretion
in tears owing to the small number of patients and to concerns that ocular
adverse effects could result from repeated tear collection within a short
interval after infusion of the drug. However, docetaxel concentrations in
tears might be higher if measured at longer intervals after administration.
Raines et al17 demonstrated that the concentration
of azithromycin in tears is highest 24 hours after administration, a sampling
time much later than that used in our study. Also, azithromycin concentrations
in tears may remain high even after the drug is cleared from the plasma. Thus,
future studies of docetaxel should be designed so that tear samples are collected
at various intervals after its administration to determine when the maximum
concentration is achieved and how long the drug remains in tears.
As stated in our previous articles on this topic, the best way to prevent
irreversible damage to the tear drainage apparatus during docetaxel treatment
is to provide close monitoring by an ophthalmologist and specific evaluation
of the nasolacrimal ducts using probing and irrigation.3-5
These measures will allow for the early identification of anatomic narrowing
of the canaliculi and nasolacrimal ducts as well as early stenting of the
ducts to prevent their complete closure during continued treatment with docetaxel.
AUTHOR INFORMATION
Submitted for publication March 7, 2002; final revision received May
15, 2002; accepted May 23, 2002.
Corresponding author and reprints: Bita Esmaeli, MD, Ophthalmology
Section, Department of Plastic Surgery, Box 443, University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: besmaeli{at}mdanderson.org).
From the Ophthalmology Section, Department of Plastic Surgery (Drs
Esmaeli and Ahmadi), the Department of Breast Medical Oncology (Drs Rivera
and Valero and Ms Jackson), and the Department of Experimental Therapeutics
(Dr Newman and Ms Hutto), the University of Texas M. D. Anderson Cancer Center,
Houston.
REFERENCES
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1. Hudis CA, Seidman A, Crown JP, et al. Phase II and pharmacologic study of docetaxel as initial chemotherapy
for metastatic breast cancer. J Clin Oncol. 1996;14:58-65.
ABSTRACT
2. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel: a new highly effective antineoplastic
agent in the management of patients with anthracycline-resistant metastatic
breast cancer. J Clin Oncol. 1995;13:2886-2894.
ABSTRACT
3. Esmaeli B, Valero V, Ahmadi MA, Booser D. Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized
side effect. Ophthalmology. 2001;108:994-995.
FULL TEXT
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ISI
| PUBMED
4. Ahmadi MA, Esmaeli B. Surgical treatment of canalicular stenosis in patients receiving docetaxel
weekly. Arch Ophthalmol. 2001;119:1802-1804.
FREE FULL TEXT
5. Esmaeli B, Hortobagyi G, Esteva F, et al. Canalicular stenosis secondary to weekly docetaxel: a potentially preventable
side effect. Ann Oncol. 2002;13:218-221.
FREE FULL TEXT
6. Lifshitz M, Weinstein O, Gavrilov V, et al. Acetaminophen (paracetamol) levels in human tears. Ther Drug Monit. 1999;21:544-546.
FULL TEXT
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ISI
| PUBMED
7. Brenner R, Cooper TB, Yablonski ME, et al. Measurement of lithium concentrations in human tears. Am J Psychiatry. 1982;139:678-679.
FREE FULL TEXT
8. Monaco F, Mutani R, Mastropaolo C, Tondi M. Tears as the best practical indicator of the unbound fraction of an
anticonvulsant drug. Epilepsia. 1979;20:705-710.
ISI
| PUBMED
9. Steele WH, Stuart JFB, Whiting B, et al. Serum, tear and salivary concentrations of methotrexate in man. Br J Clin Pharmacol. 1979;7:207-211.
ISI
| PUBMED
10. Tondi M, Mutani R, Mastropaolo C, Monaco F. Greater reliability of tear versus saliva anticonvulsant levels. Ann Neurol. 1978;4:154-155.
11. Monaco F, Piredda S, Mastropaolo C, Tondi M, Mutani R. Diphenylhydantoin and primidone in tears. Epilepsia. 1981;22:185-188.
ISI
| PUBMED
12. Tondi M, Mutani R, Mastropaolo C, et al. Greater reliability of tear versus saliva anticonvulsant levels. Ann Neurol. 1978;4:154-155.
13. Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst. 1991;83:288-291.
FREE FULL TEXT
14. Jones DT, Monroy D, Pflugfelder SC. A novel method of tear collection: comparison of glass capillary micropipettes
with porous polyester rods. Cornea. 1997;16:450-458.
ISI
| PUBMED
15. Nakajima M, Susumu Y, Kenji S, et al. Assessment of drug concentrations in tears in therapeutic drug monitoring,
I: determination of valproic acid in tears by gas chromatography/mass spectrometry
with EC/NCI mode. Ther Drug Monit. 2000;22:716-722.
FULL TEXT
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ISI
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16. Van Agtmaal EJ, van Haeringen NJ, Bloem MW, et al. Recovery of protein from tear fluid stored in cellulose sponges. Curr Eye Res. 1987;6:585-588.
ISI
| PUBMED
17. Raines DA, Yusuf A, Jabak MH, Ahmed WS, Karcioglu ZA, El-Yazigi A. Simultaneous high-performance liquid chromatography analysis of azithromycin
and two of its metabolites in human tears and plasma. Ther Drug Monit. 1998;20:680-684.
FULL TEXT
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ISI
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