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DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 9
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considerably different. These and other considerations, contrary to the
suggestion of Lin et al., have not yet allowed development of a
substantiated and valid model to describe accurately drug elimination
by the intestine after both oral and intravenous administration.
Several experimental findings, some of which we described (6),
support our original assumptions and conclusions. For example, the
hepatic clearance of midazolam—a drug that like nifedipine is completely metabolized mainly by CYP3A and also has an intermediate
hepatic clearance—was estimated from in vitro measurement of its
microsomal intrinsic clearance and appropriate scale-up to the whole
organ (7). Comparison of this value with the drug’s estimated systemic clearance after intravenous administration showed excellent
agreement, leading to the conclusion that the contribution of intestinal
CYP3A to midazolam’s elimination from the systemic circulation was
negligible (7). Subsequent studies performed during the anhepatic
phase of liver transplantation confirmed this by finding that intestinal
clearance of midazolam in the systemic circulation contributed on
average ,10% to the overall clearance of the drug (1). Moreover,
pharmacokinetic analysis identical to that used by us to separate the
relative contributions of intestinal and hepatic metabolism to nifedipine’s first-pass effect, also concluded that intestinal extraction is a
major factor in midazolam’s bioavailability after oral administration,
along with that by the liver (5). The same approach has also been
applied to cyclosporin. Moreover, recently published data indicate
that P-glycoprotein–mediated active secretion of drugs into the intestinal lumen might contribute to drug elimination in addition to intestinal CYP3A4 [for review, see Wacher et al. (8)]. Many substrates of
CYP3A4 are also transported by P-glycoprotein, and both proteins are
induced by rifampin (9). Assessment of intestinal drug metabolism
derived from in vitro data as suggested by Lin et al. does not take this
fact into account.
In summary, the model provided by Lin et al. is of theoretical
interest. Considering that this model neglects the physiology of the
gastrointestinal tract, it is not surprising that experimental and clinical
data published do not support the approach by Lin et al.
Medizinische Klinik
(N.H., E.E.O., H.H.),
Klinikum der
Christian-AlbrechtsUniversität zu Kiel and
Dr. Margarete Fischer-BoschInstitut für Klinische
Pharmakologie (M.F.F., H.K.K.)
1110
NORBERT HOLTBECKER
MARTIN F. FROMM
HEYO K. KROEMER
EDGAR E. OHNHAUS
HUGO HEIDEMANN
References
1. M. F. Paine, D. D. Shen, K. L. Kunze, J. D. Perkins, C. L. Marsh, J. P.
McVicar, D. M. Barr, B. S. Gillies, K. E. Thummel: First-pass metabolism of midazolam by the human intestine. Clin. Pharmacol. Ther. 60,
14 –24 (1996).
2. M. F. Hebert, J. P. Roberts, T. Prueksaritanont, and L. Z. Benet: Bioavailability of cyclosporine with concomitant rifampin administration is
markedly less than predicted by hepatic enzyme induction. Clin. Pharmacol. Ther. 52, 453– 457 (1992).
3. M. F. Fromm, D. Busse, H. K. Kroemer, and M. Eichelbaum: Differential
induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 24, 796 – 801 (1996).
Downloaded from dmd.aspetjournals.org at ASPET Journals on April 29, 2017
First-pass metabolism after oral drug administration does not only
occur in liver, but also in epithelial cells of the gut wall mucosa [e.g.
with the cytochrome P4503A4 (CYP3A4) substrates cyclosporin and
midazolam]. For example, 43% of an intraduodenally administered
dose of midazolam was extracted in intestinal mucosa in patients
during the anhepatic phase of a liver transplantation, proving the
importance of intestinal drug metabolism for low bioavailability of
midazolam (1). Moreover, induction of intestinal metabolism of
CYP3A4 substrates, such as cyclosporin and verapamil, was the major
reason of reduced bioavailability of these drugs during coadministration of the enzyme-inducing agent rifampin (2, 3). These observations
are in accordance with a marked increase in CYP3A content in
intestinal epithelial cells during administration of rifampin to healthy
volunteers (4).
Using a standard pharmacokinetic approach, which has been used
for the estimation of intestinal and hepatic metabolism of cyclosporin,
midazolam, and verapamil (2, 3, 5), we identified rifampin-induced
prehepatic metabolism of the CYP3A4 substrate nifedipine as a major
factor for reduced bioavailability during coadministration of rifampin
to healthy volunteers (6).
These findings have been challenged by Lin et al. They present
model simulations that confirm the well-known principle that enzyme
induction in the liver and/or intestine has a greater effect on AUC after
oral than intravenous administration, and this is more pronounced the
higher the drug’s intrinsic clearance(s) (CLint). Thus, Lin et al. correctly point out that a larger change in AUCpo than AUCiv after
enzyme induction does not necessarily indicate greater enzyme induction in the intestine than in the liver—a conclusion that we reached
regarding the interaction between rifampin and nifedipine (6). In
reaching this conclusion, we assumed that nifedipine’s systemic clearance after an intravenous dose only reflects hepatic elimination and
that metabolism of systemically available drug by intestinal enzymes;
in this case, CYP3A localized in the enterocyte is negligible. Lin et al.
consider this not to be a valid assumption that leads to erroneous
estimates of the extraction ratios of the intestine (EQ) and liver (EH).
Modeling drug elimination by an organ such as the liver, where the
vascular supply and metabolizing enzymes are intimately associated
within the sinusoidal architecture, has been relatively successful (7).
The well-stirred model applied by Lin et al. has, in fact, been widely
used when considering organ elimination in the context of whole body
pharmacokinetics. However, it is important to note that less success
has been achieved as the level of functional reality has increased (i.e.
the well-stirred model does not describe intraorgan characteristics and
events very well). Given the different anatomy and vascularity of the
intestine relative to the liver, application of the model to describe drug
metabolism within this organ is not the trivial and simple extension
provided by Lin et al. For example, after oral administration, absorbed
drug undergoes vectorial transport in which it is first exposed to
metabolizing enzymes such as CYP3A in the enterocytes of the
microvilli before reaching the villous capillaries. On the other hand,
for drug in the systemic circulation, the reverse pathway must be
traversed. Unfortunately, the fraction of the mesenteric blood supply
delivering drug to the enterocytes is not well-established, and it also
varies, dependent on physiological factors (including digestion).
Moreover, diffusion of drug from the villous capillaries to enzyme
located at the apex of the enterocyte must occur. Thus, exposure of
absorbed and systemic drug to the metabolizing enzyme may be
LETTER TO THE EDITOR
4. J. C. Kolars, P. Schmiedlin-Ren, J. D. Schuetz, C. Fang, and P. B.
Watkins: Identification of rifampin-inducible P450IIIA4 (CYP3A4)
in human small bowel enterocytes. J. Clin. Invest. 90, 1871–1878
(1992).
5. K. E. Thummel, D. O’Shea, M. F. Paine, D. D. Shen, K. L. Kunze, J. D.
Perkins, and G. R. Wilkinson: Oral first-pass elimination of midazolam
involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Pharmacol. Ther. 59, 491–502 (1996).
6. N. Holtbecker, M. F. Fromm, H. K. Kroemer, E. F. Ohnhaus, and H.
Heidemann: The nifedipine-rifampin interaction: evidence for induction of gut wall metabolism. Drug Metab. Dispos. 24, 1121–1123
(1996).
1111
7. K. E. Thummel, D. D. Shen, T. D. Podoll, K. L. Kunze, W. F. Trager,
P. S. Hartwell, V. A. Raisys, C. L. Marsh, J. P. McVicar, D. M. Barr,
J. D. Perkins, and R. L. Carithers, Jr.: Use of midazolam as a human
cytochrome P4503A probe. I. In vitro-in vivo correlations in liver
transplant patients. J. Pharmacol. Exp. Ther. 271, 549 –556 (1994).
8. V. J. Wacher, L. Salphati, and L. Z. Benet: Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Del. Rev.
20, 99 –112 (1996).
9. E. G. Schuetz, W. T. Beck, and J. D. Schuetz: Modulators and substrates
of P-glycoprotein and cytochrome P4503A coordinately up-regulate
these proteins in human colon carcinoma cells. Mol. Pharmacol. 49,
311–318 (1996).
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