Download pharmacokinetic profile and comparative bioavailability

Yeyet Cahyati Sumirtapura, dkk.
Urinary Excretion Profiles of Four Oral Cephalosporins in
Indonesian Healthy Subjects
Yeyet Cahyati Sumirtapura1, Jessie Sofia Pamudji1, Ingriyani N.2, Wibawati Sulistiyo2,
Herwanto Suhalim2
1
Department of Pharmacy, Bandung Institute of Technology, Jl. Ganesa 10 Bandung
40132 Indonesia.
2
PT. Sanbe Farma, Bandung, Indonesia.
(Received 7th April 2004; Accepted 1st Juni 2004)
Abstract
To provide pharmacokinetic data of antibiotics in Indonesian subjects, used for the
treatment of urinary tract infections, urinary excretion profiles of four oral cephalosporins
(cefadroxil, cephalexin, cefuroxime axetil, and cefixime) were studied in Indonesian
healthy volunteers following single dose administration of each drug. The doses adminis
tered were 500 mg (one capsule) for cefadroxil, 500 mg (one tablet) for cephalexin, 500 mg
(one tablet) for cefuroxime axetil, and 100 mg (two capsules of 50 mg) for cefixime. Each
drug was administered at fasting state, except for cefuroxime axetil which was administered concomitantly with meal. Urine samples were collected up to 12 hours following drug
intake. The drug concentrations in urine samples were determined by a reversed phase high
performance liquid chromatography. Within the first 10-hours after drug intake more than
90% of the doses administered were excreted unchange for cefadroxil and cephalexine,
yiel-ding in maximum drug concentrations (in urine) ranging from about 500 µg/ml to
6000 µg/ml (depending on urine volume excreted), which were achieved 2 to 4 hours after
drug administration. Cefuroxime was partially metabolized in the body and only about 50%
of the dose administered were excreted unchange in urine within the first 10 hours after
drug intake; maximum urine concentrations, varied from about 150 µg/ml to 3000 µg/ml,
were reached 2 to 6 hours after the drug intake. After administration of cefixime, about
30% of the active compound were recovered in the urine. The urinary excretion profiles of
the four cephalosporins were comparable to those obtained previously by other authors in
different ethnics.
Keywords: Cephalosporins, cefadroxil, cephalexin, cefuroxime axetil, cefixime, urinary
excretion, Indonesian subjects.
Abstrak
Untuk memperoleh data farmakokinetika antibiotik, dalam mengobati infeksi saluran urin,
pada subyek orang Indonesia, profil ekskresi empat sediaan oral sefalosporin (sefadroksil,
sefaleksin, sefuroksim aksetil, dan sefiksim) diteliti pada sukarelawan orang Indonesia
sehat yang diberi dosis tunggal salah satu obat tersebut. Dosis yang diberikan adalah 500
mg (satu kapsul) untuk sefadroksil, 500 mg (satu tablet) untuk sefaleksin, 500 mg (satu
tablet) untuk sefuroksim aksetil, dan 100 mg (dua kapsul masing-masing berisi 50 mg)
untuk sefiksim. Masing-masing obat diberikan pada keadaan puasa, kecuali untuk
sefuroksim aksetil yang diberikan bersamaan dengan makanan. Sampel urin ditampung
50 - Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004
Yeyet Cahyati Sumirtapura, dkk.
selama 12 jam sesudah pemberian obat. Konsentrasi obat dalam sampel urin ini ditentukan
secara kromatografi cair kinerja tinggi fase balik. Selama 10 jam setelah pemberian obat,
lebih dari 90% dosis yang diberikan diekskresi dalam bentuk yang utuh untuk sefadroksil
dan sefaleksin; konsentrasi maksimum kedua zat tersebut dalam urin berkisar antara 500
sampai 6000 µg/ml (tergantung pada volume urin yang diekskresi) yang tercapai 2 sampai
4 jam setelah pemberian obat. Sefuroksim sebagian dimetabolisme dalam tubuh dan hanya
sekitar 50% dari dosis yang diberikan diekskresi dalam urin dalam bentuk yang utuh
selama 10 jam pertama setelah pemberian obat; konsentrasi maksimum obat dalam urin
beragam dari sekitar 150 sampai 300 µg/ml yang tercapai sekitar 6 jam setelah pemberian
obat. Setelah pemberian sefiksim, sekitar 30 % senyawa aktif tersebut ditemukan kembali
dalam urin. Profil ekskresi keempat macam sefalosporin tersebut dalam urin sama dengan
yang dihasilkan pada ras lain yang diperoleh oleh penelitian-peneliti lain.
Kata kunci : Selosporin, sefadroksil, sefaleksin, sefuroksim aksetil, sefiksim, ekskresi
uriner, subyek orang Indonesia.
Introduction
Cephalosporins or cephem antibiotics are semisynthetic antibiotics derived from
cephalosporin C, a natural antibiotic produced by the mold Cephalosporium acremonium. Cephalosporins are bactericidal and, similar to penicillins, they act by
inhibiting the synthesis of bacterial cell wall. Chemical modification of positi-ons 3
and 7 has resulted in a series of drugs with different characteristics [1]. Up to now
there are more than 20 cephalosporin antibiotics marketed in Indonesia [2].
Certain cephalosporins are used for urinary tract infections (UTI) as alternatives
when resistance to commonly used antibacterials occurs (1). Antibacterials used to
treat urinary-tract infections need to be excreted in adequate urinary concentrations. Some oral cephalosporins used for UTI are cefadroxil, cephalexin, cefuroxime axetil, and cefixime. These drugs were reported to be excreted in urine as
unchanged compound in high amount.
At present, drug dosage regimen designed for western countries (based on the
pharmacokinetic data resulted from the corresponding ethnics) are directly applied
to other countries including Indonesia without considering the possibility of the
presence of ethnic variability in drug pharmacokinetics which may be potentially
to occur. Several authors have reported the evidence of pharmacokinetic differences between Caucasian and Asian peoples (especially Indonesians) [3-4].
Up to now there has been no information about the pharmacokinetics, especially a
urinary excretion profile, of cephalosporin antibiotics in Indonesian subjects. The
aim of this research is to study urinary excretion profiles of four oral cephalosporins in Indonesian subjects in order to provide pharmacokinetic data for these drugs
in the corresponding ethnic which will be important as a basis in achieving rational
therapy of urinary tract infections in Indonesian patients and in emphasizing costActa Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004 - 51
Yeyet Cahyati Sumirtapura, dkk.
effective strategies that may be particularly important in the coming era of pharmaceutical care.
Experimental
Urine collection
Urine samples for cefadroxil, cefuroxime axetil and cefixime studies were
collected for bioequivalence studies during the drugs development by a domestic
company, namely: Cefat® 500-mg capsule for cefadroxil with Duricef® 500-mg
capsule as the reference product, Anbachim® 500-mg (BN F-4B-0800) for
cefuroxime axetil with Zinnat® 500-mg tablet (BN C014785) as reference product,
and Sporetik® 50-mg capsule (BN 1297855 B) for cefixime with Cefspan® 50-mg
(BN 921010) as the the reference product. All of the drugs were given a single dose
(500 mg for cefadroxil and cefuroxime axetil, and 100 mg for cefixime) in six
healthy Indonesian subjects with a two weeks interval. Cefadroxil and cefixime
were administered in fasting state while cefuroxime axetil with meal.
Urine samples for cephalexin were collected to study the urinary excretion profile
of this drug in Indonesian subjects. A single dose of drug of 500 mg (Ospexin®
tablet, BN FAB 0101 lot 110027) was given to six Indonesian healthy subjects in
fasting state.
All of the subjects participating in the studies were healthy and normal men, age
between 20 and 40 years, with average weight of 60 kg and average height of 162
cm. For all of the studies, urine samples were collected up to 10 hours after the
drug administration. The samples were kept frozen at –20º C until analysis.
Analytical methods
For all of the drugs, their concentrations in urine samples were determined by a
reversed phase HPLC method using a C-18 column as the stationary phase.
Cefadroxil, cefixime and cephalexin were determined as unchanged compounds,
while cefuroxime axetil (as pro drug) was determined as cefuroxime (active
compound). The detection was performed by a spectrophotometrically at 229 nm
for cefadroxil, 286 nm for cefixime, 274 nm for cefuroxime, and 254 nm for
cephalexin. Sample preparation (prior to HPLC assay) involved liquid-liquid
extraction with an ethylacetate for cefuroxime and cefixime, while that for cefadroxil and cephalexine urine samples were simply diluted with a mobile phase (should
be mentioned) and centrifuged to separate solid materials.
Data analysis
Drug concentration data was transformed to drug amount by multiplying drug
concentration with urine volume of each urine sample. These data were then
52 - Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004
Yeyet Cahyati Sumirtapura, dkk.
transformed to fraction and cumulative amount excreted (as percent of dose
administered) by taking into account the dose administered.
Results and discussion
Urine volume data, drug concentrations, fractions excreted and cumulative urinary
excretions of each drug are presented in Tables 1-4 and Figures 1-3. It showed that
each drug has different pharmacokinetic characteristics. Cefadroxil and cephalexin
attained very high concentrations in urine (exceeded 2000 µg/ml) which was
reached within 0-2 hours period after drug intake for cephalexin and within 2-4
hours for cefadroxil. These data indicated that cephalexin was absorbed more
rapidly than cefadroxil. With the same dose, cefuroxime reached the maximum
urine concentration of about 800 µg/ml during 2-4 hours, while cefixime reached
maximum concentration of about 650 µg/ml during 4-6 hours after drug administration.
Figure 1 show that urinary concentrations of cefixime decreased more slowly
compared to those of three other cephalosporins. During 8-10 hours period, urinary
concentration of cefixime was still more than 250 µg/ml, while those of cefadroxil
and cephalexin were already decreased until about 50 µg/ml. In fact, plasma data
during bioavailability studies of the drugs indicated that cefixime was eliminated
from the body with longer elimination halflife compared to cefadroxil and
cefuroxime.
2500
Concentration (ug/ml)
2000
1500
Cefadroxil
Cephalexin
Cefuroxime
Cefixime
1000
500
0
0 -- 2
2 -- 4
4 -- 6
6 -- 8
8 -- 10
Excretion periode (hours)
Figure 1. Urinary concentration-time profile of each antibiotic after the administration
of their preparations in a single dose of 500 mg.
Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004 - 53
Yeyet Cahyati Sumirtapura, dkk.
Table 1. Average urinary excretion data of cefadroxil after single dose administration of CFT-500 and DCF-500 in male healthy volunteer
Time
periode
Urine volume
(ml)
(hours)
I
0-2
144 + 114
2-4
205 + 227
4-6
180 + 111
6-8
184 + 140
8 - 10 348 + 162
0 - 10 1062 + 418
Drug concentration
(µg/ml)
I
II
588 + 543
939 + 995
2226 + 1552 2172 + 1428
552 + 162
782 + 510
291 + 151
231 + 131
54 + 30
87 + 66
II
117 + 91
171 + 130
209 + 166
135 + 68
222 + 115
854 + 265
Drug amount
(mg)
I
87.4 + 118.9
227.3 + 93.5
87.9 + 42.1
43.0 + 30.7
16.6 + 10.1
463.2 + 25.5
Drug amount
(% Dose)
II
73.1 + 89.7
236.0 + 73.7
96.5 + 45.1
31.3 + 21.5
16.4 + 12.3
453.3 + 26.3
I
17.5 + 23.8
45.5 + 18.7
17.6 + 8.4
8.6 + 6.1
3.3 + 2.0
92.6 + 5.1
II
14.6 + 17.9
47.2 + 14.7
19.3 + 9.0
6.3 + 4.3
3.3 + 2.5
90.7 + 1.0
Cumulative amount
(% Dose)
I
II
17.5 + 23.8 14.6 + 17.9
62.9 + 10.7 61.8 + 10.2
80.5 + 7.7 81.1 + 3.5
89.2 + 3.7 87.4 + 4.1
92.6 + 4.6 90.7 + 5.3
I = CFT-500 ; II = DCF-500
Table 2. Average urinary excretion data of cephalexin after a single dose administration of Ospexin 500 in male healthy volunteer
Time
periode
(hours)
Urine
volume
(ml)
0-2
2-4
4-6
6-8
8 - 10
0 - 10
384 + 279
320 + 86
202 + 102
138 + 104
275 + 135
1320 + 409
Drug
concentration
(µg/ml)
2083 + 2292
429 + 269
155 + 87
136 + 111
47 + 20
35 + 17
54 - Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004
Drug amount
(mg)
Drug amount
(% Dose)
Cumulative amount
(% Dose)
285 + 79
125 + 50
27 + 8
17 + 9
10 + 6
462 + 22
57.0 + 14.5
24.5 + 9.6
5.0 + 1.3
3.5 + 1.6
2.0 + 1.1
92.5 + 4.4
57.0 + 14.5
81.9 + 6.8
87.0 + 6.2
90.4 + 4.9
92.5 + 4.4
92.5 + 4.4
Yeyet Cahyati Sumirtapura, dkk.
Table 3. Average urinary excretion data of cefuroxime after a single dose administration of ABM-500 and ZNT-500 in male healthy volunteer
Time
Period
Urine volume
(ml)
(hours)
I
0–2
241 ± 210
2–4
309 ± 296
4–6
222± 125
6–8
190 ± 130
8 – 10 139 ± 156
0 – 10 1090 ± 823
II
276 ± 280
209 ± 204
206 ± 145
216 ± 122
187 ± 132
1062 ± 572
Drug concentration
(µg/ml)
I
II
84.8 ± 104.4 46.1 ± 76.4
844.0 ± 972.1 609.8 ± 436.5
469.5 ± 353.9 656.4 ± 566.7
219.4 ± 168.7 229.4 ± 205.9
131.8 ± 93.2 99.6 ± 83.7
Drug amount
(mg)
I
15.8 ± 17.8
118.3 ± 77.9
78.4 ± 50.9
33.4 ± 24.2
12.5 ± 8.2
257.4 ± 71.6
Drug amount
(% Dose)
Cumulative amount
(% Dose)
II
I
II
14.1 ± 26.5 3.2 ± 3.6
2.8 ± 5.3
90.5 ± 49.8 23.7 ± 15.6 18.1 ± 10.0
88.5 ± 47.6 15.7 ± 10.2 17.1 ± 9.5
41.0 ± 33.1 6.7 ± 4.9
8.2 ± 6.6
12.2 ± 6.6
2.5 ± 1.7
2.4 ± 1.3
243.1 ± 52.6 51.5 ± 14.3 48.6 ± 10.5
I
3.2 ± 3.6
26.8 ± 14.6
42.5 ± 14.0
49.2 ± 14.1
51.5 ± 14.3
II
2.8 ± 5.3
20.7 ± 13.2
38.4 ± 11.0
46.6 ± 11.1
48.6 ±10.5
I = ABM-500 ; II = ZNT-500
Table 4. Average urinary excretion data of cefixime after a single dose administration of SPK-50 and CFN-50 in male healthy volunteer
Time
period
(hours)
0-2
2-4
4-6
6-8
8 - 10
0 - 10
Urine volume
(ml)
I
161 ± 192
181 ± 201
181 ± 211
127 ± 84
146 ± 89
796 ±776
Drug concentration
(µg/ml)
II
I
II
86 ± 38
23.6 ± 15.7 18.8 ± 12.8
84 ± 67 96.0 ± 100.6 56.5 ± 37.0
88 ± 39 133.2 ± 108.5 88.1 ± 36.1
153 ± 132 92.3 ± 79.8 94.6 ± 64.7
147 ± 121 56.6 ± 45.7 43.2 ± 22.9
559 ± 332
Drug amount
(mg)
I
3.17 ± 3.06
6.16 ± 2.42
8.27 ± 2.98
7.75 ± 2.95
5.55 ± 2.46
30.91 ± 7.41
II
1.46 ± 0.71
3.78 ± 1.89
7.29 ± 2.61
8.83 ± 3.24
4.75 ± 1.86
26.11 ± 5.25
Drug amount
(% Dose)
I
3.17 ± 3.06
6.16 ± 2.42
8.27 ± 2.98
7.75 ± 2.95
5.55 ± 2.46
30.91 ± 7.41
II
1.46 ± 0.71
3.78 ± 1.89
7.29 ± 2.61
8.83 ± 3.24
4.75 ± 1.86
26.11 ± 5.25
Cumulative amount
(% Dose)
I
3.17 ± 3.06
9.34 ± 5.03
17.61 ± 6.04
25.36 ± 6.46
30.91 ± 7.81
II
1.46 ± 0.71
5.24 ± 2.03
12.53 ± 3.92
21.36 ± 4.59
26.11 ± 5.25
I = SPK-50 ; II = CFN-50
Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004 - 55
Yeyet Cahyati Sumirtapura, dkk.
100
Fraction excreted (%)
80
60
Cefadroxil
Cephalexin
40
Cefuroxime
Cefixime
20
0
0 -- 2
2 -- 4
4 -- 6
6 -- 8
8 -- 10
Excretion periode (hours)
Figure 2. Fraction of dose of each drug excreted in urine during the first 10-hours
after the administration of their preparations in a single dose of 500 mg
.
Cumulative amount excreted (%)
100.0
80.0
Cefadroxil
Cephalexin
Cefuroxim e
91.792.5
90.4
88.3
87.0
81.9
80.8
Cefixim e
62.4
60.0
57.0
47.9
50.1
40.5
40.0
28.5
23.8
20.0
23.4
16.1
15.1
7.3
3.0 2.3
0.0
2
4
6
8
10
Time (hours)
Figure 3. Cumulative amount of each drug excreted in urine during the first 10-hours after
the administration of their preparations in a single dose of 500 mg.
The cumulative amount of drugs excreted in the urine until 10 hours after the drug
intake indicate that cefadroxil and cephalexine have a good bioavailability when
given orally and have been eliminated from the body mainly by renal excretion.
The amount s of drugs excreted unchanged during the first 10 hours for both drugs
were about 90% of dose administered, about 50% for cefuroxime and about 30%
for cefixime. The lowest amount of drug recovered in urine for cefixime was due
56 - Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004
Yeyet Cahyati Sumirtapura, dkk.
to poor bioavailability of the drug when given orally. Faulkner et al. [5] re-ported
the absolute bioavailability of cefixime is about 50% when given orally.
Compared to the results obtained in western countries, the results of this study
indicate that the urinary excretion profiles of the four oral cephalosporins in
Indonesian subjects are comparable to those observed for western people as reported previously by several authors [5-12].
Conclusion
From the results obtained in this study, the following conclusions may be drawn:
(i) The four cephalosporins have different pharmacokinetic characteristics,
particularly in terms of relative bioavailability, absorption rate, route of elimination and elimination rate; (ii) The urinary excretion profiles of the drugs in Indonesian subjects are comparable to those obtained in other ethnics, especially in
western people.
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58 - Acta Pharmaceutica Indonesia, Vol. XXIX, No. 2, 2004