Brief report: Gastrointestinal secretion of ciprofloxacin

Brief Report: Gastrointestinal Ciprofloxacin

Secretion of

Evalaati& of the Charcoal Model for Investigations in Healthy Volunteers FRITZ SORGEL, Ph.D. Nijmberg Federal Repubiic of Germany KURT G. NABER, M.D. Straubing, federal Republic of Germany ULRICH JAEHDE, Ph.D. Niirnberg federal Republic of Germany ANDREAS REITEP, B.Sc.Essen, federal Republic of Germany ROBERT SEELMANN, &SC. Niirnberg Federal Republic of Germany GABRIELE SIGL, M.D. Straubing, Federal Republic of Germany

he primary route of excretion of the new fluoroT quinol,ones is by the kidneys. Renal excretion of unchanged drug is greatest for ofloxacin, whereas other agents such as pefloxacin and difloxacin are. excreted unchanged by’ the kidney only in very small amounts [1,2]; Little is known about the excretion of unchange’d fluoroquinolones and their metabolites into feces. Ciprofloxacin’s elimination from the body is mostly renal, but there is significant nonrenal excietion of the drug, approximately 40 to 45 percent of an administered dose [l-3]. Studies with intrivenous administration of radioactive carbon-14 ciprofloxacin by Beermann et al [4] revealed that in healthy human volunteers about 17.8’ percent of the total radioactivity could be found in the feces, whereas 71.0 percent was foutid in urine. Chromatographic separation of urine samples further revealed that 13.4 percent of the total radioactivity was metabolites and in feces the percentage of metabolites was found to be 14.6 percent. From these data, it is evident that about 10 percerit of an intravenous dose is excreted into the fee& by partially’ unknown mechanism(s). 0ti th& basis of the known mechanisms of physiologic. disposition of drugs in the body, biliary and gastroifitestinal elimination are the most likely nonrenal pathways of elimination of ciprpF;;c$ that leads to the reported amounts of the drug Studies with ciprofloxacin revealed that .following intravenous administration qfzarbon-14 ciprofloxacin to rats., considerable radioactivity may be found in the gastromtestirial mucosa and’gastrointestinal contents [51. At least pati of this radioactivity may be from biliary excretion, which herein is not considered to be gastrointestinal secretion.” The .data published so far have been obtained in ilitact animals only; Radioactivity found in the’ lower parts of the gastrointestinal tract shortly after injection and before any excretions by the ‘biliary tract could have entered the lower part may be an important hint for gastrointestinal secretion in that part of the &ut. Shortcomirigs of experiments using laboratory animals are the obvipus interspecies differences of that elimination pathway’ itself, and significant species differences of the hepatic metabolism leaving vakiable amounts of unchanged compound for gastrointestirial secretion. This always limits considerably the quantitative extrapalatjon of such data to humans. I 1

Perioperative chemoprophylaxis in abdominal surgery with intravenous antibiotics such as ciprofloxatin, and asservation of tissue samples of the gut for subsequent analysis of the active compound, may be used to qualitatively estimate the potential secretion of the agent into the gut. The analysis of such samples will not allow other than an indirect conclusion that a transfer from blood into the gut occurs. No quantitative information may be obtained from such measurements. The limitations of these two major attempts to study the important question of gastrointestinal secretiion of ciprofloxaciri as described earlier are obvious and prompted us to consider other models, preferably ones that use healthy human subjects. The models should allow a quantitative estimation of gastrointestinal secretion and should use the intact gtietrointestinal tract. Furthep requirements for a valid model are homogeneity of the population, which also SUPports the idea of using healthy volunteers. METHODS AND .RE&JLTS . Tw&e healthy volunteers received ciprofloxacin as an intravenous 200-mg dose with and without oral charcoal co-treatment. Urine was collected hourly until six hours and-then as shown in Figure 1. The amount of unchanged ciprofloxacin in .grine was assayed by high-performance liquid chromatography [6]. Urinary excretion per unit time was calculated by determining the concentration and multiplying it by the urine Volume. Statistics’were done by analysis of valiance and Scheff6 test. Theoretical Considerations

On the basis of the clearance concept, the following assumptions were mad6 to allow the quantitation of the gastrointestinal secretion of ciprofloxacin in htimans from simple urinary excretion data. The total elimination capacity of an agent is estimated by its ‘tot+ clearance by the falloying (Equation I): Cltot = dose/AUC, where Cl,,, = total clearahce and AUC = the area under the curve. The total clearance consists of renal (Cl,,) and nonrenal clearance (Cl,,,,) as follows (Equation II): CL, = a,, pathways consist The CL,,, and partially gastrointestinal (Cl,,,) not yet established as follows (Equation III): amm

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=

Clhep

+

+ ale,. of mostly hepatic (Cl,,,) (Cl,,,,) as well as other pathways of elimination,

c&as,

+

Clother.

SYMPOSIUM

ON CIPROFLOXACIN

i SiiRGEL ET AL

1

O-2

2-4

4-6

CLren = Clhep + cl,astThe gastrointestinal clearance in the intact body consists of gastrointestinal secretion (Cl,,,) and reabsorption (Cl reabs)as follows (Equation V): Cl,ast = CL - CLhs. Note that we define reabsorption clearance as a new term that counteracts Cl,,, and must therefore have a negative sign. The term, clearance, may be justified since it “clears” an agent from the gastrointestinal content and the absorption sites, respectively. Introducing Equation V into Equations II and IV yields the following (Equation VI): clren

+

Clhep

+

TT T-r

8-12

12-16

24-36

16-24

36-48 -I

For ciprofloxacin, Clother seems to be very small and probably negligible. Thus nonrenal clearance reduces to the following (Equation IV):

=

T, T-r

Time (h)

Figure 1. Cumulative urinary excretion of clprofloxacin with and without charcoal treatment.

cl,,,

6-8

T

cl,ec

-

C1reabs.

Figure 2 shows how the administration of charcoal affects the transit of ciprofloxacin into and from the gastrointestinal tract into blood. In the normal situation (Figure 2, top) when ciprofloxacin is administered intravenously, it is taken up by epithelial cells of eliminating organs such as those of the kidney or gastrointestinal tract mucosa. In the kidney it has been shown that the transfer from the blood into tubular fluid is active and therefore energy-consuming [7]. Although this has not yet been proved, it is reasonable to assume that the uptake and/or release by cells of the gastrointestinal tract is also active [81. Our present knowledge of gastrointestinal secretion obtained from animal studies and human studies involving gastrointestinal surgery as described earlier suggests that many parts of the gut (proved for the colon) can se-

Crete ciprofloxacin [9]. As Figure 2, top, shows for the normal situation, any ciprofloxacin secreted into the lumen of the gut may be subject to reabsorption. This reabsorption may, however, occur in the duodenum to the highest extent and be nearly absent in the colon [lO,ll]. The pharmacokinetics in this situation include the processes of secretion and reabsorption. When charcoal is administered on a second occasion (Figure 2, bottom) under otherwise identical conditions, any ciprofloxacin that has been secreted will not be reabsorbed, since we could show in in vitro experiments that more than 99 percent of ciprofloxacin will be bound to charcoal. As no reabsorption occurs, the term Clreabs in Equations V and VI is canceled. Assuming that the intestinal secretion of ciprofloxacin is an active process and that the hepatic and renal clearance was not affected by charcoal, the total clearance increases according to Equations VII and VIII are, without charcoal (-ch) (Equation VII): CL-ch)

=

cl,,,

+

Clhep

+

c1,,,

-

Clreabs,

and with charcoal (+ch) (Equation VIII): Cl,,,(+ch) = Cl,,, + Clhep + Cl,,,. Under these assumptions, clearance total (-t-ch) is greater than clearance total (-ch) and the increase in Cltot reflects at least most of the reabsorption of ciprofloxacin. Using Equation VII in Equation VIII yields (Equation IX): Cl,,,(+ch) = CM-ch) + C1reai.x. According to Equation I, the increase in total clearance by charcoal administration causes AUC(+ch) to be smaller than AUC(-ch). If Cl,,, does not change and AUC decreases, then according to Equation X:

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SYMPOSIUM

ON CIPROFLOXACIN

Blood

n -O-

/SdRGEL

ET AL

Mucosa

-

Gastrointestinal

Lumen

Gastrointestinal

Lumen

Drug Passive transport Active transport Blood

Mucosa

n n

.

n

“ID I

n

+mm

n

Charcoal

n

D

#

m 9,

n

n n

n

.m

l

$

.rn n U

Drug Passive transport Active transport

Figure 2 Transrt of clprofloxacln from blood Into the gastrorntestrnal tract and from the gastrolntestlna tract Into blood without (top) and with (bottom) charcoal treatment

aY.,, = amount excreted (from zero to time x)/ACC (from zero to time x),

changed ciprofloxacin decreases by 13 mg, which is 6.5 percent of the dose when ciprofloxacin is administered together with charcoal.

then the amount of ciprofloxacin excreted unchanged has to decrease accordingly. COMMENTS Furthermore, the attempt to quantify gastrointestinal secretion must consider the extent of absorption of The measurement of nonrenal routes of elimination ciprofloxacin from the gastrointestinal tract. Previous in humans poses many problems, since unlike renal studies by our group and others have shown that the clearance there is no direct sampling of most extrareabsorption of ciprofloxacin from tablets is between 60 nal pathways of elimination. It should always be kept and 70 percent 11,Zl. The exact bioavailability of se- in mind that the term, nonrenal clearance, is indicreted ciprofloxacin is not known, but taking the re- rectly calculated and depends on plasma level measult of 60 percent bioavailability of our study, Clreab surement and on the accurate collection of urine. The must be multiplied by 1.66, since Equation VI as- measurement of nonrenal excretion pathways, and sumes 100 percent reabsorption. A further complicaeven biliary excretion, may in humans not give the tion of the charcoal model is that any ciprofloxacin in true result, since bile sampling may not be complete. the lower gastrointestinal tract will not even be reabIt is still impossible to quantitate gastrointestinal sorbed in the normal situation. secretion of drugs in humans, even when invasive methods are involved. Thus, indirect methods are necExperimental Data essary and have been used in this study. We applied As shown in Figure 1, the renal excretion of un- the basic equations of the clearance concepts and asSA-64s

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SYMPOSIUM

sumed that ciprofloxacin is secreted by the gastrointestinal tract. This procedure allowed us to conclude that secretion of ciprofloxacin into the gut may be made by measurement of the renal excretion of unchanged ciprofloxacin with and without charcoal treatment. The assumptions that were made to establish this are, for the most part, experimentally proved or highly evident from pharmacokinetic principles. An important assumption that needs to be verified is the absence of a direct effect of charcoal on the gastrointestinal secretion of ciprofloxacin. This important question cannot be answered presently and could not be determined for many other drugs studied previously. Therefore, the mechanism of charcoal effects on gastrointestinal clearance of drugs is not yet fully understood. The formation of a gradient from blood into the gut is an explanation often used. In our model, however, we were not assuming gradient formation as the relevant mechanism. Alternatively, active secretion of ciprofloxacin from the blood into the gut was the basis of our calculations. At a blood pH of 7.4, the anionic form of ciprofloxacin dominates [8]. This would be in accordance with data by Lauterbach 181showing that the duodenal or jejunal mucosa can actively secrete anions. The drug can be secreted in its base form as well and this may therefore contribute in part to ciprofloxacin’s gastrointestinal elimination. The quantitation of gastrointestinal secretion of ciprofloxacin including the absence of complete reabsorption as described earlier suggests that at least 10.6 percent of intravenously administered ciprofloxacin is taken up by the epithelial cells of the gut and secreted into the gut lumen.

November

ON ClPROFLOXAClNISliRGEL

ET AL

ACKNOWLEDGMENT This article is dedicated to U. Stephan, M.D., Professor and Chairman of the Department of Pediatrics, University of Essen, Federal Republic of Germany, on the occasion of his 60th birthday. We thank R. Metz, Institute for Biomedical and Pharmaceutical Research, Numberg Heroldsberg, for helpful suggestions regarding the manuscript. REFERENCES 1. Sorgel F: Metabolrsm of gyrase inhlbrtors. Rev Infect Dis 1989: 2 (suppl 5): 1119-1129. 2. Sergei F, Naber KG, Mahr G, Stephan U: Pharmacokrnetics of enoxacin: camparlson with other qurnolones. Postgrad Medicine 1989, (In press). 3. Sorgel F, Naber KG, Stephan U: Pharmakokinetik and Analybk “on Gyrase-Hemmern. 1. Pharmakokinetik van Gyrase-Hemmern-ein Uberblrck. FAC Fortschr Antimikr Antlneoplast Chemother 1987; 6-10: 1907-1961. 4. Beermann 0, Scholl H, WIngender W, ei a/: Metabolism of ciprofloxacin in man. In. Proceedings of the 1st International Ciprofloxacin Workshop, Leverkusen, 1985. 5. Siefert HM, Maruhn D, Scholl H: Pharmacokinetics of ciprofloxacrn. Distribution to and elimination from tissues and organs following single or repeated admrnistration of clprofloxacin In albino rats. ArznermittelforschiDrug Res 1986; 36 (II): 1503-1510. 6. Sorgel F, Muth P, Mahr G, Manoharan M: Pharmakokinetrk und Analytik von GyraseHemmern. 2. Hochdruckflusslgkertschromatographrsche Analybk [HPLC) van GyraseHemmern rn blologrschem Material. FAC Fortschr Antrmikr Aniineoplast Chemother 1987; 6-10. 1963-1986. 7. Sdrgel F, Jaehde U, Naber KG. Stephan U: Pharmacokrnetrc drsposition of qulnolones In human body flurd and tissues. Clinical Pharmacoklnetrcs 1989; 16 (suppl): 5-24. 8. Lauterbach F: Intestinal secretion of organic ions and drugs. In: Kramer M, Lauterbach F, eds. Intestinal permeatron. Proceedings of the 4th Workshop Conference Hoechst, Schlob Rersensburg, 1975. Excerpta Medica, Amsterdam, 19n; 173-195. 9. Darner A, Wrtthohn A, Kraas, E: Brief Report Crprofloxacin prior to colon surgery. In: Proceedings of Ciprofloxacrn: Major Advances in Intravenous and Oral Quinolone Therapy. Naples, Florida, 1989. 10. Van Saene JJM, Van Saene HKF, Gertz JN, et al: Quinolones and colontratron resrstante in human volunteers. Pharmaceutisch Weekblad Screnbfrc Edition 1986; 8: 67-71. 11. Staib AH, Beerman D, Harder S, Fuhr U, Liermann D: Absorptron drfferences of cipro. floxacrn along the human gastrointestinal tract determrned using a remotecontrol drug &&very device (HF-capsule). Am .I Med 1989; 87 (suppl 5A) 5A-66S-5A-69s.

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