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Departments of Biochemistry & Molecular Biology & Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute, Little Rock, AR 72205 and * Department of Pediatrics and Pharmacology, University of Missouri at Kansas City and Division of Pediatric Clinical Pharmacology and Toxicology, The Children’s Mercy Hospital, Kansas City, MO 64108-9898
4To whom correspondence should be addressed. E-mail: mockdonaldm{at}uams.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • biotin • pharmacokinetics • pigs • tissue distribution • metabolites
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,2)
as follows: 1) infusion of an
antibody against a tumor antigen, which has been previously coupled to
streptavidin, 2) infusion of biotin linked via galactose to
human serum albumin to act as a clearing agent for the
antibody-streptavidin conjugate, and 3) infusion of
biotin linked to either a radioimaging nuclide such as
111In or radiotherapy nuclide such as
90Y via dodecane tetraacetic acid. Such
information is of potential use not only for comparison of the
pharmacokinetics of the radionuclide-linked biotin molecule, but
because of indirect implications concerning biotin uptake into the
cell, which may occur via a biotin transporter such as the one recently
described from our laboratory or via the sodium-dependent
multivitamin transporter (3
,4)
. Ideally, the pharmacokinetics and metabolism of biotin would be studied directly in humans using stable isotope–labeled biotin in physiologic amounts; however, stable isotope-labeled biotin is not available. Moreover, analytical methods (e.g., HPLC/mass spectrometry) suitable for separation and quantitation of stable isotope–labeled biotin have not been published to date. An alternative approach would be to conduct pharmacokinetic and metabolic studies using pharmacologic amounts of biotin. In such studies, the endogenous plasma concentrations of biotin are negligible for at least the first several hours after a bolus infusion. To extrapolate from pharmacokinetic doses to physiologic doses, one must assume that pharmacologic amounts of biotin do saturate the normal mechanisms for absorption, distribution or clearance of biotin. To test that assumption, we adopted a two-step approach. First, we conducted studies in an animal model using radionuclide-labeled biotin to characterize the pharmacokinetics and metabolism of biotin at tracer and physiologic doses. Second, we are continuing human studies using unlabeled biotin in pharmacologic amounts. This paper reports the results of our animal studies that used tracer and physiologic doses.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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D-[8,9-3H(N)]Biotin with a specific activity
of 1.7 TBq/mmol was purchased from DuPont NEN (Boston, MA).
D-[Carbonyl-14C]biotin with a specific
activity of 2 GBq/mmol was purchased from Amersham (Arlington Heights,
IL). The purities of both were consistently >98% by HPLC.
Radiolabeled biotin was diluted in normal saline before use.
Radioisotope-labeled forms of biotin were used to trace specific
metabolic fates while avoiding the confounding effects of dietary
biotin or biotin synthesized by intestinal bacteria. The 3H
labels for [3H]biotin are at positions 8 and 9 of the
valeric acid side chain (in the ß position relative to the carboxyl
group). Thus, the 3H labels are lost from the major
molecule in the conversion of biotin to bisnorbiotin as
[3H]acetate and 3H-water. This loss of the
label limits the ability to follow the production of bisnorbiotin and
other side-chain metabolites (e.g., bisnorbiotin sulfoxide,
tetranorbiotin or tetranorbiotin sulfoxide) from
[3H]biotin. In contrast, [14C]biotin is
labeled at the carbonyl carbon of the ureido group in the bicyclic ring
and is not lost during metabolism to bisnorbiotin (5)
. The
synthesis of [14C]bisnorbiotin has been described
elsewhere (6
7
8)
.
Animals and diets.
Male Landrace-Cambrough cross piglets (Tyson, Springdale, AR) 2 mo
of age and weighing 9–13 kg, underwent surgical insertion of two
indwelling venous cannulas, one in the external jugular and the other
in the femoral vein. The piglets had free access to water and food
before and during the experiment, as described previously
(9)
. Animal protocols were approved by the University of
Arkansas for Medical Sciences Animal Care and Use Committee.
Determination of protein binding of biotin in pig plasma.
Two different methods were used to determine the proportion of biotin
bound reversibly to macromolecules (presumably proteins) in pig plasma.
The first method was ultracentrifugation using an Amicon Centrifree
device (Millipore, Amicon Division, Danvers, MA) with 30,000 MW
cut-off membrane. Plasma (1 mL) was incubated with 500 fmol of
[3H]biotin for 5 min before molecular-sieve
separation of the macromolecules from the smaller molecules. To
determine the concentration of free [3H]biotin and total
(bound plus free) [3H]biotin, aliquots of the
ultrafiltrate and starting plasma were counted in triplicate using
liquid scintillation counting (Tri-Carb 1900-TR, Packard Instruments, Meridian, CT). The percentage of bound biotin was calculated as the
concentration of total biotin minus the concentration of free biotin
divided by the concentration of total biotin as previously published
(10)
.
The second method was rapid equilibrium dialysis using an equilibrium dialysis apparatus (Spectrum Medical Industries, Laguna Hills, CA). Teflon cells with a 12,000–14,000 MW cut-off membrane were used. Plasma (1 mL), preincubated with 1000 fmol of [3H]biotin for 60 min, was added to the "donor" side of the membrane; 1 mL of PBS, pH 7.4, was added to the "acceptor" side. The samples were rotated at 30 rpm in a 30°C water bath for 5 h. Concentrations of 3H in aliquots from the acceptor side and from the starting plasma were determined in triplicate by liquid scintillation counting as described above. Attainment of equilibrium was ensured by choice of a dialysis interval of at least twice the time to reach a stable distribution of the radioactivity between the dialysis compartments as previously determined empirically. The percentage bound was calculated as the concentration in the starting plasma biotin divided by two (for the 1 mL of plasma on the donor side and 1 mL of buffer on the receptor side) minus the concentration of the free biotin divided by the concentration of the total biotin (adjusted for 2-mL volume).
Measurements of total radioactivity and biotin metabolite profile in plasma.
Blood samples were collected in heparin at a series of time points
during the experiment. Plasma was separated from RBC by centrifuging at
2600 x g at 20°C for 10 min. Plasma was assayed
immediately or stored frozen at -70°C until use. Plasma
concentration of radioactivity was determined in triplicate by liquid
scintillation counting as described above. Plasma proteins were removed
using an Amicon Centrifree ultrafiltration device at 1500 x g at 20°C for 45 min. Radiolabeled biotin and biotin
metabolites in plasma ultrafiltrate were separated by HPLC and
quantitated by radiometric flow detection as described previously
(8
,11
,12)
.
Pharmacokinetic analysis.
For each piglet, pharmacokinetic analysis of the curves of measurements
of plasma concentration of radioactivity vs. time was performed using
curve-fitting algorithms (Kinetica version 2.0) resident in the
SIPHAR computer program (SIMED, Creteil, Cedex, France). Initial
polyexponential parameter estimates were generated using a peeling
algorithm with correction for infusion time. Final parameter estimates
were generated with the use of a nonlinear, weighted, least-squares
algorithm with weight set as the reciprocal of the calculated plasma
concentration. The evaluation of the best fit for a given data set was
based on the examination of the Akaike information criterion
(13)
and the coefficient of variation for the
polyexponential parameters estimated from a mono-, bi- and
triexponential curve fit of each data set. Rate constants of each phase
were then determined from the best fit of a given data set. The area
under the plasma concentration vs. time curve
(AUC)5
was calculated using the linear trapezoidal rule and was then
extrapolated to infinity (AUC
) by using each individual
piglet’s values. Both the total plasma clearance (CL), mean residence
time (MRT), and apparent steady-state volume of distribution
(Vdss) were determined from the AUC using standard
pharmacokinetic equations.
Distribution of [14C]biotin in tissues.
Pigs were killed on d 4 after administration of [14C]biotin. Organs (kidney, lung, heart, duodenum, brain and liver) and gluteus muscle were harvested. Representative samples (n = 3) from each organ were dissolved in Solvable (DuPont NEN Research Products, Boston, MA). Tritium and 14C were determined by liquid scintillation as described above. The percentage dose in each organ or tissue was determined by multiplying the percentage dose per gram by the organ weight. Muscle was assumed to be 60% of total body weight.
Statistical methods.
In each study, simple means of the pharmacokinetic parameters were calculated for each pig studied; variance around the means are expressed as the standard deviation (x ± 1 SD). For determination of the statistical significance of differences between groups containing paired values (e.g., biotin binding measured by two methods), Student’s two-tailed, paired t test was used. For determination of the significance of differences between groups in which values were not paired or repeated (comparison of pharmacokinetic parameters between isotopes or between groups of animals), Student’s two-tailed, unpaired t test was used. The critical value for P was chosen to be 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using the ultracentrifugation method, the percentage bound was 6.9 ± 1.2% with a range of 5.1–8.7% (n = 6). Using equilibrium dialysis, the percentage bound was 7.6 ± 3.4% (n = 5) with a range of 2.9–11.1%. The differences are neither significant (by t test) nor biologically important. Overall, the studies provide evidence that the percentage of bound biotin is routinely small with respect to free biotin. Accordingly, no correction was attempted to account for biotin binding to plasma protein in the pharmacokinetic analysis.
Biotin and metabolite profiles in plasma.
We observed previously that substantial amounts of biotin metabolites
were excreted in swine urine, collected for 0–12 h after the
intravenous infusion of either [3H]biotin or
[14C]biotin (9)
. Rapid elimination
of 3H radioactivity was also observed in pilot
studies using [3H]biotin. This rapid
elimination of 3H radioactivity from plasma and
the early excretion of biotin metabolites in urine raised the question
whether rapid metabolism of biotin (i.e., < 1 h) would result in
significant concentrations of radiolabeled biotin metabolites in
plasma, thus introducing artifacts in a pharmacokinetic analysis of
total 3H data. Thus, we initially sought to
determine whether total plasma concentration of
3H provides a good approximation of biotin
remaining in plasma. If not, does 14C provide an
accurate estimate of [14C]biotin disappearance?
In these studies, a mixture of a tracer dose of
[3H]biotin and a physiologic dose of
[14C]biotin was given as an intravenous bolus
to three pigs. The infused dose of [3H]biotin
was 0.12 nmol/kg body, a value <1% of the daily dietary intake of 330
nmol/d. The dietary intake in this study was estimated from consumption
of 450 g pig ration/d by pigs weighing 
10 kg; labeled biotin
content of SGR (Clover Brand, Farmland Industries, Kansas City, MO) is
735 pmol/g. Thus the amount of [3H]biotin
infused was indeed a tracer dose.
As depicted in Figure 1A
, [3H]biotin rapidly disappeared.
Biotransformation was rapid as evidenced by the appearance of the
metabolite [3H]acetate (or
3H-water) in plasma as early as 5 min after the
injection (Fig. 1B
). The contribution of
[3H]biotin sulfoxide was minor with respect to
[3H]biotin throughout the study (Fig. 1C
). However, the contribution of
[3H]acetate increased to exceed that of
[3H]biotin after 2 h. Not surprisingly,
the total plasma concentration of 3H did not
accurately track the time course of [3H]biotin.
Due to the contribution of [3H]acetate,
pharmacokinetic analysis did not agree well between
[3H]biotin and total tritium (data not shown).
Pharmacokinetic disappearance curves for
[3H]biotin were well fit by a
three-compartment, open model.
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41 µmol biotin/kg body
(5
,14)
.
After [14C]biotin infusion,
[14C]biotin disappeared rapidly (Fig. 2A
). Each of the three curves exhibited an excellent fit to a
triexponential function. Bisnorbiotin and biotin sulfoxide were the two
major biotin metabolites detected in pig plasma (Figs. 2B
and C
, respectively), but those metabolites accounted for
only minor amounts of radioactivity in two of the three pigs.
Bisnorbiotin methylketone, an intermediate in biotin ß-oxidation, was
also detected in very small amounts (<1%, data not shown).
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depicts the disposition curves of total
14C radioactivity for the individual pigs #1–3.
Each exhibited an excellent fit to a triexponential function. We found
no significant difference between the mean of the elimination
half-life times derived from true
[14C]biotin vs. those derived from total
14C radioactivity for either the 
, ß or 
phases (Table 1). We conclude that the plasma concentration of total
14C radioactivity is a good approximation of true
[14C]biotin in plasma.
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After confirming that the disposition of 14C radioactivity accurately reflects the disappearance of [14C]biotin in pig plasma, a study was conducted to characterize more accurately the early pharmacokinetics using more frequent early sampling. This was made possible by drawing smaller blood volumes and determining only the disposition of 14C radioactivity. A physiologic dose of [14C]biotin (88 ± 19 nmol/kg body, 2.5 times the daily dietary intake) was injected intravenously in five pigs. Samples were collected at eight intervals over the first 60 min and at a total of 16 intervals over 48 h.
The data are depicted in a semilogarithmic format in Figure 3
. Once again, the data exhibited an excellent fit to a triexponential
equation (Table 2
). The pharmacokinetic parameters of this second study agreed reasonably
well with those obtained from the study with less frequent sampling
(Table 1)
.
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This third study investigated whether the transition from pharmacologic
and physiologic doses of [14C]biotin to tracer
doses of [3H]biotin produced any striking
differences in pharmacokinetics for the early phase of disappearance.
Tracer amounts of [3H]biotin (0.03, 0.1 and 0.2
nmol/kg body, which are all <1% of average daily dietary intake) were
administered intravenously. Blood samples were collected at 13 time
intervals over 12 h (16 intervals over 48 h for Pig 11). Only
total radioactivity was measured; insufficient blood was available to
differentiate between [3H]biotin and its
metabolites. The mean plasma disappearance curves (Fig. 4
) exhibited a good fit to a triexponential equation, but heterogeneity
from pig to pig was evident. The AUC did not appear to increase
proportionally with dose. Pharmacokinetic parameters from this tracer
study are summarized in Table 3
. The half-life of disappearance for the compartment was not
significantly different for the study of three pigs at tracer doses of
[3H]biotin compared with the half-life
for the study of five pigs with pharmacokinetic doses of
14C (Table 2)
. Because of the rising contribution
of
[3H]acetate/[3H]H20
to total [3H] radioactivity, half-lives of
disappearance for the ß and compartments were significantly
different, although physiologically similar.
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Table 4
summarizes the distribution of radioactivity in organs and muscle from
the five pigs that received physiologic doses of
[14C]biotin and from two of the three pigs that
received tracer doses of [3H]biotin. Most of
the administered radioactivity accumulated in the liver. Muscle
contained 10–23% of infused radioactivity, assuming that muscle mass
was 60% of the body weight. Accumulation of radioactivity in the
kidney varied from 2.8 to 6.4% of the injected radioactivity. Heart,
lung, brain and duodenum each contained <1% of the administered
radioactivity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However, neither Recommended Dietary
Allowances (15)
nor Recommended Daily Intakes
(16)
have been formulated. One impediment to formulating
Adequate Intakes and Recommended Daily Intakes is limited data on
bioavailability. Although information on the bioavailability of biotin
given in pure form is emerging (17)
, there is little
information about the bioavailability of protein-bound biotin,
which is the predominant dietary form.
A better understanding of biotin pharmacokinetics and metabolism would
be useful in investigating bioavailability. Moreover, the usefulness of
the plasma concentration of biotin as an indicator of biotin
nutritional status remains unclear, and a better understanding of
biotin pharmacokinetics would help in determining blood sampling times
relative to meals and fasting in studies of biotin status. Finally, the
recent tumor imaging and radioimmunotherapy techniques that utilize the
infusion of radionuclide-conjugated biotin might be enhanced by a
more detailed knowledge of biotin pharmacokinetics, both at the
physiologic doses characteristic of imaging (18)
and at
the pharmacologic doses characteristic of radiotherapy
(1
,2)
.
The egg white–fed rat is the most commonly studied animal model of
biotin deficiency. Although the metabolism of radiolabeled biotin
injected intraperitoneally in rats resembles biotin metabolism in
humans, (5
,12)
, anticonvulsant treatment in rats did not
reproduce the accelerated biotin biotransformation that had been
observed previously with anticonvulsant treatment in both adults and
children (19
,20)
. Moreover, blood volumes available from a
single animal are small relative to what is required to measure biotin
and its metabolites, given the specific activities of commercially
available radiolabeled biotin.
Instead, we chose the pig as the model for this study. The pig is often
an appropriate animal model for studying the digestion and absorption
of nutrients in humans and for evaluating the biotransformation of
therapeutic drugs (21
22
23
24
25
26)
. The metabolism of xenobiotics
in piglets is often similar to that seen in human infants. Piglets have
amounts of cytochrome P450, cytochrome
P450 reductase, glucuronyl transferase,
aminopyrine demethylase and analine hydroxylase that are similar to
those of human neonates and infants in both activity (21
, 24)
and developmental regulation (25)
. Moreover, in
our recent study, the urinary biotin metabolite profile in pigs closely
resembled the human urinary biotin metabolite profile (9)
.
Because biotin cannot be synthesized by mammals, it must be transported
from the sites of absorption in the small and large intestine to the
tissues by either blood or lymph. The current assumption is that biotin
is transported primarily in plasma and RBC. Investigators disagree
concerning whether biotin is primarily free in aqueous solution in
human plasma or bound (reversibly or covalently) to plasma
macromolecules such as proteins (27)
. Our previous studies
indicated that biotin exists mainly in free form in human plasma
(10)
and reversibly bound biotin accounts for <10% of
the total pool of free and reversibly bound biotin (28)
.
Our studies in rabbits also indicated that <10% of biotin is bound to
plasma protein (29)
. In cattle, a low percentage of biotin
is probably bound, as judged from the relatively short elimination
half-life of 10 h and the short MRT of 8 h
(30)
. To have unambiguous interpretations of plasma
concentrations of radiolabeled biotin, we initially studied protein
binding of biotin in pig plasma. In this study, biotin binding in pig
plasma determined by ultracentrifugation and rapid equilibrium dialysis
were 6.9 and 7.6%, respectively. Results obtained from these two
methods agree well and provided evidence that the reversible binding of
biotin to pig plasma protein is minimal and thus can be largely ignored
in the determination of plasma biotin pharmacokinetics.
[3H]Biotin is available commercially at a high specific activity, allowing the administration of tracer doses. However, the radiolabels in [3H]biotin are lost after the first cycle of ß-oxidation of the valeric acid side chain. The cleaved acetate fragment may enter the metabolic cycle and be converted into [3H] metabolites; the 3H elutes with the solvent wave front, consistent with either [3H]acetate or 3H2O. Given that these products are smaller and more polar than bisnorbiotin and biotin sulfoxide, it is not surprising that [3H]acetate (or 3H-water) apparently reentered blood more quickly than either bisnorbiotin or biotin sulfoxide. Thus, although [3H]biotin is useful for measuring the disappearance of biotin, the appearance of [3H]acetate in the plasma and urine introduces artifacts into the estimate of biotin pharmacokinetics based on total 3H. This can be avoided if sufficient blood is available that the 3H metabolites can be resolved from [3H]biotin by HPLC. Even this HPLC separation does not provide information concerning the appearance of bisnorbiotin or its subsequent metabolites such as bisnorbiotin sulfoxide.
For [14C]biotin, the 14C
label resides in the carbonyl carbon in the ureido group of the ring
structure. The complex ring structure remains intact during
ß-oxidation, and the 14C label is retained on
each of the metabolites. The specific radioactivity of commercially
available [14C]biotin is relatively low. To
achieve sufficient 14C concentration in blood,
the studies described here required administration of at least
"physiologic" amounts (1% of body pool); these are no longer
tracer doses. Nevertheless, coadministration of
[14C]biotin and
[3H]biotin provided complementary information
on pharmacokinetics and metabolism.
The disposition curves from both of the
[14C]biotin studies were best characterized by
a triexponential function, which supports use of a
three-compartment open model (Fig. 5
) to describe biotin disposition. The very short half-life of the
initial distribution phase (7 min) and first elimination phase (1.4 h)
as well as the rapid appearance of
[3H]acetate/H2O are all
novel findings and indicate a more rapid disappearance of biotin from
swine plasma than previously appreciated. The rapid disappearance
likely is not the result of metabolism. Rather, the initial, rapid
phase likely reflects the rapid (i.e., minutes vs. hours) distribution
of biotin from the central compartment (i.e., the plasma water space)
to the peripheral compartments (e.g., total body water pool or tissue
pools). Biotin requirements are likely influenced by the distribution
of this vitamin to the sites at which it associates and is utilized
(e.g., incorporated into carboxylases) and possibly stored. Binding to
a transporter and subsequent uptake are but one example of the complex
processes that likely affect the disappearance curve. A
sodium-dependent multivitamin transporter has recently been
discovered, cloned and sequenced (4
,31)
. In addition to
pantothenic acid and lipoic acid, this protein transports biotin and is
widely expressed. On this basis, Prasad and co-workers
(4)
proposed that this protein is the biotin transporter.
Our group has also discovered and characterized a biotin transporter in
human lymphocytes (3)
. On the basis of pharmacokinetic
considerations (32)
, we speculated that this transporter
was distinct and was primarily responsible for biotin transport into
lymphocytes and perhaps other tissues such as hepatocytes
(33
,34)
.
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and C
and the parameters for
the pigs in Table 2
). We also observed that the extent of catabolism
varied substantially among individuals, at least as judged by
metabolite profiles (8
,35)
.
The rapid disappearance of biotin may have been masked in previous
animal and human studies as the result of two factors. This study used
intravenous infusion rather than oral administration, which avoided the
slow process of gastrointestinal absorption (36
,37)
. This
study used radioactive tracers in physiologic doses coupled with HPLC
rather than microbial assays; this allowed specific detection of biotin
and its metabolites (30
,36
,37)
. Despite these limitations,
disappearance curves after intravenous biotin in pharmacologic amounts
to cows exhibited a good fit to a three-compartment model with a
terminal elimination half-life of about 8 h (30
, 38)
.
The apparent terminal elimination half-life for biotin, 22 h,
is relatively long. Given the fact that the CL for biotin in piglets
[0.46 L · (h · kg)] was relatively rapid, we speculate that
the long apparent terminal elimination half-life is most likely the
consequence of slow reequilibration from a "deep tissue" pool
caused by extensive tissue binding of the vitamin (including covalent
binding) especially to carboxylases and perhaps histones
(39)
. The observation that biotin accumulated primarily in
the liver, muscle and kidney, organs rich in biotin-dependent
enzymes, is consistent with this speculation. The volume of
distribution at steady state (Vdss) does not
represent a physical fluid space. Rather, this number is calculated as
the biotin dose divided by the product of the area under the
disappearance vs. time curve and the terminal rate constant of
disappearance. For both drug and vitamin pharmacokinetics, tight
binding to proteins outside the plasma is often associated with volumes
of distribution at steady states that are too great to correspond to
any fluid space. The Vdss values for biotin
observed in our experiments (7–130 L/kg) are too large to represent a
fluid space, but consistent with a deep tissue pool. We speculate that
the retention over many days of a substantial portion of the
administered dose occurs as a consequence of the metabolic trapping of
biotin by one or more of the following three processes: 1)
transport of biotin into cells, 2) conversion of biotin to
intermediates such as biotinyl-AMP and biotinyl-CoA, and
3) binding of biotin to proteins such as carboxylases and
histones.
The similarity of the pharmacokinetics between the tracer doses and physiologic doses observed in our studies provides evidence that the metabolic pathway for biotin was not saturated by the physiologic dose and that the physiologic doses reflect the disposition that would be seen for endogenous biotin and dietary biotin given in typical amounts. Whether the same pharmacokinetic behavior would be observed at pharmacologic doses of biotin remains to be determined.
In summary, these pharmacokinetic studies revealed a very rapid disappearance of biotin administered intravenously, which is consistent with active and rapid biotransformation and surprisingly rapid reflux of acetate or H2O back into plasma. The apparent large volume of distribution and the slow terminal elimination phase for biotin reflect pharmacokinetic properties consistent with its known physiologic functions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
|---|
2 Supported by grants from the U.S. Department of Agriculture to D.M.M. (CSREES 94–34322-0353) and National Institute for Diabetes and Digestive and Kidney Diseases (R01 DK36823) to
D.M.M.
3 Current address: Witco, Akron, OH
5 Abbreviations used: AUC, area under curve; CL, plasma clearance; MRT, mean residence time; Vdss, volume of distribution at steady state.
Manuscript received September 28, 2000. Initial review completed November 30, 2000. Revision accepted January 23, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Zempleni J., Mock D. M. Uptake and metabolism of biotin by human peripheral blood mononuclear cells. Am. J. Physiol. 1998;275:C382-C388
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11. Mock D. M., Langbehn S., Mock N. I. Distribution of biotin within human milk fractions. Proceedings of North American Society of Pediatric Gastroenterology & Nutrition 1989 Chicago, IL
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