ANTIMICROBIAL AGENT8 AND CHEMOTHERAPY, Mar. 1977, p. 462-469 Vol. 11, No.

3
Copyright C 1977 American Society for Microbiology Printed in U.S.A.

Bioavailability of Tetracycline and Doxycycline in Fasted and

Nonfasted Subjects
PETER G. WELLING,* PATRICIA A. KOCH, CURTIS C. LAU, AND WILLIAM A. CRAIG
University of Wisconsin Center for Health Sciences, School of Pharmacy* and Department of Medicine, and
the Veterans Administration Hospital, Madison, Wisconsin 53706
Received for publication 22 November 1976

The influence of various test meals and fluid volumes on the relative bioavail-
ability of commercial formulations of doxycycline hyclate and tetracycline hy-
drochloride was studied in healthy human volunteers. Serum levels of tetracy-
cline were uniformly reduced by approximately 50% by all test meals, whereas
serum levels of doxycycline were reduced by 20%. The reduction of tetracycline
serum levels will likely be of clinical significance. The bioavailability of each
drug was almost identical from an oral solution and from capsules in fasted
subjects. The rate of doxycycline absorption was reduced when capsules were
administered with a small volume of water, but the overall efficiency of absorp-
tion of both drugs was essentially independent of co-administered fluid volume.
The use of 8-h serum data provides a reliable estimate of drug bioavailability for
tetracycline and, to a lesser extent, for doxycycline.
Although the tetracycline antibiotics may be tissue distribution (5, 10) and apparently longer
bactericidal to some microorganisms at high biological half-life of doxycycline (11, 22), this
concentrations, their activity is primarily bac- lipid-soluble compound appears to have several
teriostatic (14). It is therefore important that advantages over other tetracyclines. From the
circulating levels of these compounds be main- results obtained with dairy products and also
tained above the minimum inhibitory concen- specific heavy metals, it is generally considered
tration (MIC) for pathogenic organisms during that food has less influence on the absorption of
a course of treatment. In view of this, there has doxycycline than that of other tetracyclines. In
been considerable interest in factors influenc- this study, the influence of solid test meals and
ing the absorption of tetracyclines after oral fluid volumes on the bioavailability of doxycyc-
doses and the degree to which these factors line and tetracycline was examined in healthy
affect circulating levels of antibiotic. human volunteers under controlled conditions.
Inhibition of absorption of the tetracyclines
due to chelation by heavy-metal ions is exten- MATERIALS AND METHODS
sively documented (8, 12, 16, 20, 21). Inhibition
by antacid preparations is also well estab- Subjects were four male and two female healthy
lished. The latter effect appears to be due to a volunteers. Male subjects were aged between 21 and
combined influence of heavy-metal ion chela- 36 years (mean, 26) and weighed between 66 and 98
tion and also a decreased dissolution rate of kg (mean, 77). The two female subjects were aged 19
tetracycline (2) or the dosage form in which it is and 22 years and weighed 55 and 70 kg. All subjects
contained (9). Milk and other dairy products were shown by medical examination to be in good
inhibit the absorption of tetracyclines to vary- physical condition with normal blood and urine lab-
oratory values. There were no histories of drug al-
ing degrees. Rosenblatt and associates (22) re- lergies.
ported that doxycycline absorption was reduced Protocols. The protocols followed were similar to
by about 20% in the presence of skimmed milk, those described previously (26; P. G. Welling, H.
whereas the absorption of demethylchlortetra- Huang, P. A. Koch, W. A. Craig, and P. O. Madsen,
cycline was reduced by about 70%. Mattila and J. Pharm. Sci., in press). Subjects were advised
associates (18) reported 50 to 60% reduction in to take no drugs for 1 week preceding the study
bioavailability of tetracycline, oxytetracycline, and no drugs other than the required doses of doxy-
and methacycline in the presence of whole milk cycline and tetracycline during the study. Sub-
whereas the absorption of doxycycline was not jects were fasted overnight before each treatment
and were permitted to eat no food, apart from test
significantly affected. Interactions influencing meals, until 4 h after dosing. On the moming of a
the absorption of tetracyclines have recently treatment, subjects drank 250 ml of water on aris-
been reviewed (19). ing, at least 1 h before dosing. Drugs were admin-
In view of the above, and also the superior istered at 8 a.m., and blood samples (-4 ml) were
462
VOL. 11, 1977 COMPARISON OF TETRACYCLINE AND DOXYCYCLINE
taken from a forearm vein into Vacutainers contain-
ing no anticoagulant immediately before and at 0.5,
1, 2, 3, 4, 6, 8, 24, and 32 (tetracycline) or 48 (doxy-
cycline) h after dosing. Serum was separated and
deep-frozen until assayed. Assays were done within
48 h of sampling.
Treatments. The tetracycline study immediately
preceded the doxycycline study. All subjects re-
ceived all treatments in both studies with one excep-
tion. One male subject vomited when taking doxy-
cycline on an empty stomach. This subject was
therefore replaced by another of similar age, weight,
and height for the three doxycycline fasting treat-
ments. Subjects received single 500-mg doses of tet-
racycline (hydrochloride) (Achromycin, lot 416-411,
Lederle) as two 250-mg capsules or single 200-mg
doses of doxycycline (hyclate) (Vibramycin, lot
51408, Pfizer) as two 100-mg capsules. Test meals
were prepared and standardized as described previ-
ously (26). Each drug was administered as the fol-
lowing treatments: treatment 1, two capsules with
250 ml of water immediately after a standard high-
carbohydrate meal; treatment 2, two capsules with
250 ml of water immediately after a standard high-
fat meal; treatment 3, two capsules with 250 ml of
water immediately after a standard high-protein
meal; treatment 4, two capsules with 25 ml of water
on an empty stomach; treatment 5, two capsules
with 250 ml of water on an empty stomach; and
treatment 6, the contents of two capsules dissolved
in 250 ml of water taken on an empty stomach.
All subjects received the same treatment at the
same time, and at least 2 weeks were allowed be-
tween each treatment. Capsules were swallowed
whole.
Asay. Serum tetracycline and doxycycline con-
centrations were determined by the spectrofluoro-
metric method of Kohn (17) as modified by Wilson
and associates (27). Assays were carried out using
0.5 ml of serum, and volumes of all solutions and
reagents used in the assay were suitably adjusted.
Fluorescence was read on a Perkin-Elmer model
MPF-4 instrument. The excitation wavelength was
maintained at 395 nm, and emission was read at 525
nm. Both excitation and emission slits were set at 10
nm. Fluorescent response was linear over the con-
centration ranges of 0.1 to 5.0 ,lg/ml and 0.4 to 7.0
,g/ml for tetracycline and doxycycline, respec-
tively. Standard solutions of both compounds were
prepared and measured with each batch of un-
knowns to allow for slight instrument drift.
Interpretation of results. Individual serum anti-
biotic levels were fitted to equation 1, which is ap-
propriate to the pharmacokinetic one-compartment
open model, as described previously (25, 26; P. G.
Welling et al., in press).
C = VD (k e-t - e-kt) (1)
In this equation, C is the concentration of drug in
serum at any time t after dosing, F is the fraction of
the doseD that is ultimately absorbed into the circu-
lation, V is the apparent distribution volume of
antibiotic in the body, and k and K are first-order
rate constants for drug absorption and elimination,
463
respectively. Fitting of individual data sets to the
equation was improved in many cases by incorporat-
ing a lag time, to, to represent the time elapsed
between dosing and appearance of antibiotic in se-
rum. Statistical comparisons were carried out as
described previously (25, 26; P. G. Welling et al., in
press).
RESULTS
Serum levels. Mean serum concentrations of
the two tetracyclines, together with statistical
comparisons between treatments, are given in
Tables 1 and 2, and the data are summarized in
Fig. 1 and 2. Similar serum profiles were ob-
tained from all fasting treatments with both
agents. Absorption was delayed slightly when
capsules were administered with a small vol-
ume of water. This delay, reflected in the ab-
sorption rate constant and time of peak height
(Tables 3 and 4), was significant (P <0.05) for
doxycycline but not for tetracycline.
Serum levels of tetracycline after the high-
carbohydrate and high-fat test meals were re-
duced to about one-half those in fasted subjects.
Serum levels were reduced further after the
high-protein meal, but differences in serum lev-
els between nonfasting treatments were signifi-
cant only at 3 and 6 h.
Serum levels of doxycycline were reduced by
approximately 20% in nonfasted subjects. Dif-
ferences between fasting and nonfasting levels
were significant during the first 4 h after dos-
ing, but not at later times. Doxycycline serum
levels after the high-protein meal appeared to
be somewhat lower than other nonfasting lev-
els during the first 4 h after dosing, but the
differences were not significant.
Results of the pharmacokinetic analysis are
summarized in Tables 3 and 4. The adequacy of
the simple one-compartment open model to de-
scribe the serum level profiles is indicated by
the high coefficients of determination, r2. De-
spite the large differences in tetracycline serum
levels in fasted and nonfasted subjects, there
were no significant differences between treat-
ments in absorption rate constants or times of
peak serum levels. With doxycycline, however,
significant differences in these parameters
were observed in some cases between fasting
and nonfasting subjects.
The major differences in the effects of food on
both drugs were those associated with overall
absorption efficiency. For tetracycline, peak se-
rum levels, areas under serum level curves
from the time of dosing until 2, 8, and 32 h and
to infinite time, and FDIV values (the fraction
of dose absorbed expressed as a concentration in
its overall distribution volume) were all signifi-
cantly greater in fasted than in nonfasted sub-
jects. With doxycycline, however, despite a
464 WELLING ET AL. ANTIMICROB. AGENTS CHEMOTHER.

; eq eq C0 C0 Cq

+1 +1 +1 +1 +1 +1 rn +1 +1 +1 o+, o0
o +1 CD
oLo +1
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eq

C- eq

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fo o ol o o= o
z
C12
co
1 0 Oeq eq
r-q oq o- o o o o
+1 +1 +1 +1 +1 +1 A +1 +1 +1 +1 +1 +1
eq 00 r- lw I- 00 CD

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0

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.S A
A
t- o 00 0000 C
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r-
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CD 00C00 t- C0 O ,w 00
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10
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c0
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u.0)
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0)
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r. 0>0
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14cic0 6C
VOL. 11, 1977 COMPARISON OF TETRACYCLINE AND DOXYCYCLINE 465
sr

TREATMENT
4 O 1 CARBOHYDRATE
02, FAT
O 3 i PRITN
A 4' FASTN 25 wl
A 5FST
*W 250 ml
0 6 FASTING SOLUTION
w
It

9-
,C%

O0
s IS 24
TOE (Ors)
FIG. 1. Average serum levels of tetracycline.

TREATMENT
4~ O I, CARBOHYDRATE
* 2, FAT
* 3 PROTEIN
A 4 1FASTING 25 Rd
E A 5 FASTING 250 ml
0 6 sFASTING SOLUTION

8 2

cn

24 36 48
TIE (hous
FIG. 2. Average serum levels of doxycycline.

tendency for these parameter values to be
larger from the fasting treatments, differences
in values between fasted and nonfasted treat-
ments frequently failed to reach significant lev-
els.
Serum levels, peak level values, times of
peak levels, and serum half-lives in fasted sub-
jects in this study were similar to previously
reported values. Serum half-lives of doxycyc-
line were somewhat shorter than those re-
ported by some previous workers (11, 22), but
were similar to those recently obtained by Ao
and associates in normal individuals (1). The
accuracy of some of the reported longer doxy-
cycline half-lives has been questioned by Gi-
baldi (13).
466 WELLING ET AL. ANTIMICROB. AGENTS CHEMOTHER.

I w v
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ado 0
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eq t~ tl* t t l
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t~ ~ ~OD
mma
Q om-

Xg = ~t- cq (m c: Um v q t- _4 r- q CD CD
w t +1 +1 +1 +1 +1 +1 A

VZJ
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7- eq m v L 3$4 .0 1

_d
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VOL. 11, 1977 COMPARISON OF TETRACYCLINE AND DOXYCYCLINE 467
I I
j ui -; c6 - t 4 - -; ,i 6OA A A

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CD
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o6 oi o6 c; _ o6 r

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t
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s
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++ (o+
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CD a CD
C) o = ) ( +1ru
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E + N _ C +_1
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I
468 WELLING ET AL.
DISCUSSION
The results obtained in this study show that,
although the absorption of orally dosed doxy-
cycline and tetracycline is impaired in the pres-
ence of food, the degree of impairment is far
greater in the case of tetracycline. The small
influence of food on doxycycline absorption is
advantageous in view of the gastric irritation
that may occur when this drug is taken on an
empty stomach. Subjects in this study fre-
quently reported transient nausea within 30
min of taking doxycycline in the fasting treat-
ments, and one subject had to be withdrawn
because of this. These symptoms did not occur
when doxycycline was taken with food and
were not observed at all with tetracycline.
The results also show that, for both drugs,
inhibition of absorption is largely independent
of the type of meal. It is interesting that the
high-protein meal, which contained a higher
proportion of heavy-metal ions, tended to pro-
duce somewhat lower serum levels of both tet-
racycline and doxycycline than did the other
nonfasting treatments.
In other studies we demonstrated impaired
absoxption of amoxicillin trihydrate (P. G.
Welling et al, in press) and, to a lesser extent,
theophylline (25) when these drugs were ad-
ministered in solid dosage forms with small
accompanying water volumes. This may be at-
tributed to their relatively low water solubility.
Both doxycycline and tetracycline were ad-
ministered as water-soluble salts in the present
study, and changes in water volumes had only
a small influence on their overall serum level
profiles.
Several dosing and sampling methods have
been used to measure the bioavailability of tet-
racycline drug products. Brice and Hammer (6)
and Blair and associates (4) compared the bioa-
vailability of various oxytetracycline products
based on serum or blood level data collected
through 6 h after single doses. Davis and associ-
ates (7) measured blood and urine tetracycline
levels during a 96-h multiple-dosage regimen
and concluded that single-dose studies using
TABLE 5. Correlations among areas under serum level curves and also between serum levels and
areas from 0 to 48 h (doxycycline) and 32 h (tetracycline)
Parameter
Area 0 2 h vs. area 0 8 h
Area 0 2 h vs. area 0 48 (32) h
Area 0 8 h vs. area 0 - 48 (32) h
Peak serum level vs. area 0 -. 48 (32) h
2-h serum level vs. area 0 48 (32) h
8-h serum level vs. area 0 48 (32) h
ANTIMICROB. AGENTS CHEMOTHER.
relatively short sampling periods may be inade-
quate for accurate bioavailability testing. Barr
and associates (3), however, showed that re-
sults obtained from single-dose studies, using
10-h serum or 48-h urine sampling periods, ac-
curately predicted tetracycline serum levels
during multiple doses of various commercial
products.
The present study utilized only single doses,
but comparisons of data based on short and long
postdosing intervals are instructive. Correla-
tion coefficients between areas under serum
level curves and also between 2-h, 8-h and peak
serum levels and 0- to 32-h or 0- to 48-h areas
are given in Table 5. With tetracycline, good
correlations were obtained between all listed
parameters, and it appears reasonable to sug-
gest that the use of serum levels or areas under
serum level curves measured at short postdos-
ing time intervals provides a reliable estimate
of tetracycline bioavailability characteristics.
Agreement between the various parameters is
not quite as good with doxycycline, but 8-h
serum levels and 8-h areas correlate quite well
with the 0- to 48-h areas.
Clinical significance. The in vitro MICs of
most tetracyclines to susceptible bacteria range
from 0.2 to 12.5 gg/ml (15, 23). Organisms with
an MIC of 0.5 ug/ml or less are considered
highly susceptible, those with an MIC of 0.5 to
2.5 ug/ml are considered moderately suscepti-
ble, and those with an MIC of 2.5 to 5 ,g/ml are
considered slightly susceptible. Doxycycline
tends to be more active against many patho-
gens than tetracycline (22).
Based on our single-dose data, the mean tet-
racycline serum levels during a multiple-dos-
age regimen of 250 mg every 6 h would be
approximately 4.5 ,ug/ml if the drug were dosed
on an empty stomach (24). If the same regimen
were followed but the doses were taken with
meals, mean serum levels would drop to 2.4 ,ug/
ml. The nonfasting regimen might thus result
in insufficiently high circulating levels of anti-
biotic for activity against less susceptible orga-
nisms.
With doxycycline, the mean serum levels ob-
Correlation coefficient
Doxycycline Tetracycline
0.75 0.93
0.35 0.89
0.77 0.95
0.87 0.83
0.46 0.87
0.88 0.98
VOL. 11, 1977 COMPARISON OF TETRACYCLINE AND DOXYCYCLINE
tained during a multiple-dosage regimen of 200
mg/day would be approximately 4.4 ,ug/ml if
12.
the drug were dosed on an empty stomach. If
the doses were taken with meals this value 13.
would drop only slightly, to 4.0 ,ug/ml. This
small reduction in serum levels is unlikely to
14.
cause therapeutic failures. Thus the reduction
in serum levels due to food observed in this
study is likely to be of clinical significance for 15.
tetracycline but not for doxycycline.
16.
ACKNOWLEDGMENTS
This investigation was supported by Public Health Serv-
ice Grant GM 20327 from the National Institute of General 17.
Medical Sciences and by a grant from Pfizer, Inc.
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