Advanced Drug Delivery Reviews 27 (1997) 201–214

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Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery M.F. Hebert* University of Washington, Department of Pharmacy, H-375 Health Science Center, Box 357630, Seattle, WA 98195 -7630 USA Received 20 December 1996; accepted 1 February 1997

Abstract The objective of this section is to evaluate the contributions of hepatic metabolism, intestinal metabolism and intestinal p-glycoprotein to the pharmacokinetics of orally administered cyclosporine and tacrolimus. Cyclosporine and tacrolimus are metabolized primarily by cytochrome P450 3A4 (CYP3A4) in the liver and small intestine. There is also evidence that cyclosporine is metabolized to a lesser extent by cytochrome P450 3A5 (CYP3A5). Cyclosporine and tacrolimus are also substrates for p-glycoprotein, which acts as a counter-transport pump, actively transporting cyclosporine and tacrolimus back into the intestinal lumen. Traditional teaching of clinical drug metabolism has been that hepatic metabolism is of primary importance, and other sites of metabolism play a relatively minor role. It appears as though intestinal metabolism plays a much greater role in the pharmacokinetics of orally administered drugs than previously thought. Intestinal metabolism may account for as much as 50% of oral cyclosporine metabolism. There are at least two components of intestinal metabolism for cyclosporine and tacrolimus, intestinal CYP3A4 / CYP3A5 and intestinal p-glycoprotein activities. The quantity of intestinal enzymes, although highly variable, do not appear to be the key to explaining the variability of oral cyclosporine pharmacokinetics in kidney transplant patients. However, the quantity of intestinal p-glycoprotein accounts for approximately 17% of the variability in oral cyclosporine pharmacokinetics. It may be that p-glycoprotein maximizes drug exposure to intestinal enzymes, thus decreasing the importance of enzyme quantity. Since cyclosporine’s FDA approval in 1983, there have been many reports of clinically significant drug interactions of other agents when given concomitantly with cyclosporine. With the FDA approval of tacrolimus in 1994, a similar pattern of clinically significant drug interactions appears to be emerging. It seems that compounds that alter (either induce or inhibit) CYP3A4 and / or p-glycoprotein will alter the oral pharmacokinetics of cyclosporine and tacrolimus. It should be expected that, until further data are available, the drugs which interact with cyclosporine will also interact with tacrolimus.  1997 Elsevier Science B.V. Keywords: Drug interactions; CYP3A4; CYP3A5; Review; mdr1

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction ............................................................................................................................................................................ Cytochrome P450 3A4 and cytochrome P450 3A5..................................................................................................................... Cyclosporine metabolism ......................................................................................................................................................... Tacrolimus metabolism............................................................................................................................................................ Intestinal p-glycoprotein .......................................................................................................................................................... Cyclosporine transport by p-glycoprotein .................................................................................................................................. Tacrolimus transport by p-glycoprotein .....................................................................................................................................

*Corresponding author. Tel.: (206)616-5016; fax: (206)5433835. 0169-409X / 97 / $32.00  1997 Elsevier Science B.V. All rights reserved. PII S0169-409X( 97 )00043-4

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8. Effects of interacting substances on cytochrome P450 and p-glycoprotein ................................................................................... 9. Cyclosporine drug interactions ................................................................................................................................................. 10. Tacrolimus drug interactions .................................................................................................................................................. 11. Conclusion............................................................................................................................................................................ References ..................................................................................................................................................................................

1. Introduction Classic teaching of the factors that influence oral drug bioavailability have included drug solubility, membrane permeability and hepatic first pass metabolism. Discussions on the contribution of the chemical properties of the drug and formulation issues as they relate to these factors were usually included. In addition, hepatic blood flow, protein binding and hepatic intrinsic clearance were generally addressed. More recently, the contribution of intestinal metabolism and p-glycoprotein (an intestinal membrane counter-transport pump) have been recognized as being clinically important factors in the pharmacokinetics of orally administered drugs [1]. This new understanding has helped explain the high interpatient and possibly intrapatient variability in the pharmacokinetics of orally administered drugs. Cyclosporine or tacrolimus, given in combination with other immunosuppressive agents, are the basis for nearly all immunosuppressive regimens used in solid organ transplantation. The oral pharmacokinetics of these agents are highly variable. Oral bioavailabilities of both compounds are generally low (14–36% for cyclosporine [2] and 8.5–22% for tacrolimus [3]). The large heterogeneity in dosing requirements for both agents may be explained by interpatient variability in hepatic metabolism, intestinal metabolism, p-glycoprotein and absorption, as well as interactions of these drugs with others in the patients’ regimens. Early work by Kleinbloesem et al. [4] suggested a bimodal distribution of oral nifedipine (a CYP3A substrate) area under the plasma concentration–time curve (AUC) in their study of 53 healthy subjects (racial demographics were not reported). This bimodal distribution could possibly be explained by a genetic polymorphism for CYP3A activity in the intestine, for p-glycoprotein or possibly for hepatic CYP3A; however, there was no apparent difference in the terminal elimination half-life between the rapid and slow metabolizers. Schellens et al. [5] more recently found in 130 healthy Dutch subjects

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that, although there was an approximately ten-fold variability in AUC following orally administered slow release nifedipine, there did not appear to be bimodality. This variability may partially be explained by factors such as environmental exposures, diet and concomitant medications. A potential genetic polymorphism for CYP3A activity across races requires further study.

2. Cytochrome P450 3A4 and cytochrome P450 3A5 It had been previously thought that the contribution of enterocyte metabolism was minimal compared to that of hepatic metabolism. This view was based on the relative rates of metabolism in intestinal microsomes compared to hepatic microsomes. This observation may in part be explained by cytochrome P450 localization in the villi tip cells that make up a relatively small portion of total intestinal mucosa. There may also have been difficulties related to the preparation of viable enterocyte microsomes. However, Watkins et al. [6] found comparable concentrations of CYP3A in hepatic and in enterocyte microsomal preparations. CYP3A accounts for approximately 20% of the total P450 in the liver and 70% in the jejunal mucosa [6]. Although CYP3A4 appears to be expressed in all adult livers [7], CYP3A5 is only expressed in approximately 24% of adults, in whom it accounts for 15–32% of the total liver CYP3A protein [8]. Watkins et al. [9] found approximately a six-fold variability in liver CYP3A4 activity, as measured by the erythromycin breath test. Hepatic CYP3A4, whether measured by content or activity, is highly variable. It has been demonstrated that the duodenal mucosa expresses CYP3A4 [10]. Kolars et al. [11] found CYP3A4 to be the predominant CYP3A expressed in human enterocytes with a ten-fold variability in CYP3A4 concentration in five human subjects. Lown et al. [12] found a six-fold variability in CYP3A

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activity, as measured by midazolam hydroxylation, and an eleven-fold variability in CYP3A4 protein content in human intestinal biopsies. Although there was a very good correlation between CYP3A activity and CYP3A4 protein content in the intestinal biopsies (r 5 0.86), neither measurement correlated with hepatic CYP3A4 activity, as measured by the erythromycin breath test. This lack of correlation suggests the independent regulation of CYP3A in the liver and intestine. Lown et al. [12] also found that CYP3A5 was detectable in approximately 70% of the patients’ intestinal biopsies. For most agents, the possibility of intestinal metabolism contributing to drug metabolism has not been addressed. This omission has lead to the potentially false assumption that hepatic first-pass metabolism or that poor absorption are entirely responsible for low bioavailability. Watkins [13] proposed that, despite the relatively small amount of P450 in the intestinal mucosa relative to the liver, the intestine plays a major role in drug metabolism. The location of the P450, just below the microvillus border, maximizes drug metabolism as it crosses the intestinal wall. In addition, Watkins [13] suggests that the exposure of enterocytes to high drug concentrations increases the relative importance of intestinal metabolism, since CYP3A is a low-affinity, high capacity enzyme.

3. Cyclosporine metabolism Cyclosporine is a widely used immunosuppressive agent. It is produced by Tolypocladium inflatum Gams or Beauveria nivea, depending on the formulation. Structurally, cyclosporine is a lipophilic, cyclic polypeptide consisting of eleven amino acids, with a molecular weight of 1202.63 Da. Low bioavailability of the oral cyclosporine formulation, Sandimmune TM , had been thought to be due to poor oral absorption. Wu et al. [1] demonstrated, through the analysis of three cyclosporine interaction studies [2,14,15], that Sandimmune TM is at least 65% absorbed when administered orally. It appears as though the relatively low bioavailability of cyclosporine is due rather to a clinically important metabolism component which takes place in the intestine. Cyclosporine is known to be metabolized by CYP3A4 and, to a lesser extent, by CYP3A5 [12,13,16]. Since both CYP3A4 and CYP3A5 have

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been shown to exist in the intestine [12] as well as the liver [7,8], it seems reasonable that the metabolism of cyclosporine would also occur at both sites. In order to better predict individualized cyclosporine dosing requirements, efforts have been made to correlate non-invasive tests, such as the erythromycin breath test, with cyclosporine dose and the corresponding blood level [17]. The application of this test has not gained widespread use, due to the limited correlation with oral cyclosporine pharmacokinetics. Turgeon et al. [18] demonstrated a statistically significant correlation in kidney transplant patients between the apparent oral cyclosporine clearance (CL / F) and a marker of hepatic CYP3A4 activity (erythromycin breath test); however, the r 2 value for this relationship was 0.297 (i.e., only 30% of the variability in CL / F could be explained by the variability in hepatic CYP3A). The limitations in correlation are understandable since the erythromycin breath test is fairly restricted to predicting hepatic CYP3A N-demethylation. Kolars et al. [19] were able to measure the metabolites of cyclosporine (AM9 and AM4N) in the portal veins of patients during the anhepatic phase of liver transplantation. There was an interfering substance that did not allow for accurate quantitation of AM1, cyclosporine’s dominant metabolite in humans. If the rates of AM1 and AM9 formation were the same in these patients as seen in enterocyte microsomal preparations, as much as 50% of orally administered cyclosporine may be metabolized in the intestine. Webber et al. [20] demonstrated that CYP3A can be detected in microsomes made from human duodenum and ileum. In addition, these microsomes were able to metabolize cyclosporine to its three primary metabolites (AM1, AM9 and AM4N). Since intestinal metabolism appears to play a major role in oral cyclosporine pharmacokinetics, the search for non-invasive predictors for cyclosporine metabolic elimination continues. A marker that accounts for both intestinal and hepatic metabolism should give a better correlation for oral cyclosporine dosing.

4. Tacrolimus metabolism Tacrolimus is a potent immunosuppressant, isolated from Streptomyces tsukubaensis. Structurally, it has a 23-member macrolide lactone, with a molecu-

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lar weight of 803.5 Da. Tacrolimus has also been found to be metabolized by CYP3A4 [21]. Lampen et al. [22] demonstrated that tacrolimus is metabolized by both human liver and small intestinal microsomes and that similar metabolite patterns were generated in vitro by human liver and intestinal microsomes. Immunoinhibition studies demonstrated that the inhibition of CYP3A decreased tacrolimus metabolite formation. Tacrolimus metabolite formation in human intestinal microsomes varied by a factor of five. Tacrolimus metabolite formation from pig duodenal mucosa (a surrogate model for human intestinal metabolism) has been found to vary depending on the section of the gastrointestinal tract. The highest concentration of metabolites occurs in the duodenum, followed by the jejunum, ileum and colon. No tacrolimus metabolites were formed by the gastric mucosa [23]. Lampen et al. [22] also found a significant difference in the tacrolimus metabolite formation rates for males and females in human duodenal samples. Further work is necessary to determine if there is a gender effect on oral tacrolimus pharmacokinetics.

5. Intestinal p-glycoprotein P-glycoprotein is a membrane efflux pump that has been associated with multidrug resistance in tumor cells [24]. Multidrug resistance appears to be most frequently caused by an increased expression of p-glycoprotein. P-glycoprotein is thought to keep intracellular drug concentrations low by transporting the drug out of the cell [25]. Pavelic et al. [26] reported that not only is p-glycoprotein located on the surface of some tumor cells, but also on many normal tissues. Of particular clinical importance is the report of p-glycoprotein expression on small and large intestinal epithelium, bile canaliculi and kidney proximal tubules [27]. Lown et al. [27] demonstrated that the p-glycoprotein expressed in human intestine is the product of mdr1 gene expression. In addition, the ten-fold variability in p-glycoprotein levels did not appear to be due to medications or short-term diet changes in the patients or the healthy volunteers studied. This section will only focus on intestinal p-glycoprotein. Since p-glycoprotein is located on the epithelium of intestinal cells, it can act as a counter-transport pump that transports drugs back

into the intestinal lumen as they begin to be absorbed across the lumenal plasma membrane. In addition to its direct effect on net drug absorption, it is possible that p-glycoprotein also maximizes the exposure of environmental toxins, and in some cases drugs, to intestinal metabolism, and thereby protects the body from exposure. Interestingly, Lown et al. [28] found no correlation with enterocyte p-glycoprotein content and either intestinal CYP3A4 content or hepatic CYP3A4 activity (as measured by the erythromycin breath test). There was also no correlation found with age or gender. Although p-glycoprotein and CYP3A4 may work together to minimize the exposure of the body to environmental toxins, they appear to be regulated separately.

6. Cyclosporine transport by p-glycoprotein Tamai et al. [29] conducted a binding study (with membrane vesicles of multidrug resistant cells) demonstrating that cyclosporine competes for binding with vinca alkaloids for a common binding site on p-glycoprotein. Goldberg et al. [30] found that cyclosporine accumulation in multidrug resistant cells was much less than in non-multidrug resistant cells. Partial reversal of this effect was achieved with verapamil. Saeki et al. [31] confirmed this finding by demonstrating that cells transfected with p-glycoprotein on the apical surface were able to transport cyclosporine out of the cell. In addition, this process appeared to be saturable. Lown et al. [28] conducted the first study demonstrating the clinical importance of p-glycoprotein in the pharmacokinetics of oral cyclosporine. Measurements of hepatic CYP3A4 activity (erythromycin breath test) and small intestinal biopsies, to measure CYP3A4 and p-glycoprotein in the gut, were taken in nineteen kidney transplant patients. Steady-state oral cyclosporine pharmacokinetics were also performed in all subjects. It was found that 56% of the variability in apparent oral cyclosporine clearance could be explained by the variability in liver CYP3A4 activity. An additional 17% of the variability was explained by intestinal p-glycoprotein levels, which varied eightfold among the patients. The intestinal CYP3A4 levels varied ten-fold, but did not appear to influence the variability of oral cyclosporine pharmacokinetics. These results suggest that, although intestinal metab-

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olism was important, for the individuals in the study, it appears as though they had a sufficient quantity of intestinal CYP3A4 to metabolize cyclosporine. However, it was the quantity of p-glycoprotein, which enhanced drug exposure to, or the catalytic efficiency of, CYP3A4 that was important in the variability of oral cyclosporine delivery. In summary, cyclosporine has been shown to be a substrate for p-glycoprotein in what appears to be a saturable process. In addition, the transport process via p-glycoprotein may be competitively inhibited by other agents that bind to the same binding site. Intestinal p-glycoprotein content appears to be an important factor clinically in oral cyclosporine variability.

7. Tacrolimus transport by p-glycoprotein Saeki et al. [31] reported that tacrolimus is transported from cells expressing p-glycoprotein, leading to reduced intracellular concentrations. Lampen et al. [23] reported that within a system of physiologically functional pig gut mucosa (Ussing chamber), tacrolimus metabolites were present on both the serosal and mucosal sides of the preparation when drug was added to the mucosal side of the preparation. No metabolites were found on either side when tacrolimus was added to the serosal side of the preparation. The metabolite patterns generated from the pig small intestinal microsomes were similar to those generated after incubation with human small intestinal microsomes. The metabolites could reach the gut lumen side via passive or active transport processes. Since tacrolimus is a substrate for p-glycoprotein, it is likely that active transport via p-glycoprotein occurs with both tacrolimus and its metabolites. In vivo, tacrolimus metabolites formed in the gut may enter the portal circulation, or re-enter the intestinal lumen. Although a direct measurement of this process with tacrolimus has not yet been reported, it is likely to be similar to that seen with cyclosporine.

8. Effects of interacting substances on cytochrome P450 and p-glycoprotein Drug interactions can be viewed from multiple perspectives. The unexpected interactions can lead to subtherapeutic dosing in the case of enzyme induc-

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ers, or to drug toxicity with enzyme inhibitors. Sometimes, known drug interactions, such as the intentional use of enzyme inhibitors (if the inhibitor is less costly than the drug that it inhibits) can be advantageous in decreasing drug costs [32]. Combinations of interacting compounds (e.g., the addition of an enzyme inhibitor when an enzyme inducer was therapeutically necessary) could possibly be used to maintain therapeutic drug levels. The exact mechanisms of the majority of clinical drug interactions are not completely understood. Most interactions have been presumed to involve induction or inhibition of hepatic metabolism, although this may or may not be a complete or accurate assessment. Competitive inhibition of metabolism may depend on the relative affinity for binding to P450 for the compound and the interacting substance, relative concentrations of the compound and interacting substance in the endoplasmic reticulum, and the importance of P450 in the elimination of the compound. An interaction could also exist if a compound competed for binding, or induced, p-glycoprotein as well. The data available on the effects of various compounds on CYP3A and / or p-glycoprotein are limited. Evaluation of CYP3A interactions are frequently done in vitro with human or animal microsomal systems, and direct measurements are rarely done. More often, assessments are made using probe compounds for a given enzyme. Many of the studies evaluating p-glycoprotein interactions are done in vitro, in animals and / or on multidrug-resistant tumor cell lines. Although this information may correlate with in vivo effects in humans, it may not. Thus, the actual mechanisms for many of the drug interactions are still in question. Some information is available that alludes to the possible mechanisms for drug interactions with amiodarone, calcium channel blockers, macrolide antibiotics, antifungal azoles, rifampin, phenobarbital and grapefruit juice, when given concomitantly with cyclosporine or tacrolimus. The remaining part of this section will look at agents that have been reported to have clinically significant interactions with cyclosporine and / or tacrolimus. In particular, this section will focus on the effect of these agents on CYP3A and p-glycoprotein. Amiodarone is an antiarrhythmic. Its use in combination with cyclosporine or tacrolimus is predominantly an issue for heart transplant patients.

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Amiodarone has been shown to be metabolized at least in part by CYP3A4 in human hepatic microsomal fractions [33]. Amiodarone also reverses multidrug resistance in Chinese hamster ovary cells [34], inhibits p-glycoprotein in a reconstituted liposome system (p-glycoprotein uniformly in an insideout orientation) [35] and inhibits drug efflux in multidrug-resistant cancer cells [36]. Amiodarone may compete with other CYP3A4 substrates for metabolism as well as inhibit p-glycoprotein transport. The calcium channel blockers are generally used to treat hypertension. The effects of the various calcium channel blockers on CYP3A and pglycoprotein are specific to each agent. Verapamil appears to be metabolized, at least in part, by CYP3A [37]. It has also been shown to reverse multidrug resistance in Chinese hamster ovary cells [34], inhibit p-glycoprotein in a reconstituted liposome system (p-glycoprotein in a uniformly insideout orientation) [35], competitively inhibit vinblastine transport by p-glycoprotein in multidrug-resistant human cancer cells [38] and reverse multidrug resistance in vitro in mouse leukemic cells that express high levels of p-glycoprotein [39]. Verapamil also has been shown to decrease p-glycoprotein expression three-fold in a multidrug-resistant human leukemia cell line after 72 h of exposure as well as to decrease p-glycoprotein mRNA two-fold within 24 h. The effects on p-glycoprotein expression were reversed within 24 h of discontinuation of exposure to verapamil [40]. Diltiazem has been shown to inhibit vinblastine transport by p-glycoprotein in multidrug-resistant human cancer cells (although less so than with verapamil) [38] and to reverse multidrug resistance in vitro in mouse leukemic cells that express high levels of p-glycoprotein (although less efficiently than verapamil) [39]. Diltiazem had no effect on p-glycoprotein expression in human leukemia multidrug-resistant cell lines [40]. Nifedipine was less effective than verapamil as an inhibitor of vinblastine transport by p-glycoprotein in multidrug-resistant human cancer cells [38] and had no effect on p-glycoprotein expression in humanmultidrug resistant leukemia cell lines [40]. Nicardipine has been shown to inhibit p-glycoprotein function on natural killer cells [41]. Verapamil may compete with other CYP3A substrates for metabo-

lism, inhibit p-glycoprotein transport and decrease p-glycoprotein expression. Diltiazem and nicardipine also appear to inhibit p-glycoprotein. Some interacting substances, such as triacetyloleandomycin (a macrolide antibiotic), can interact via multiple mechanisms. Watkins et al. [7] demonstrated that triacetyloleandomycin increased the measured CYP3A in human liver microsomes, but had low activity for erythromycin demethylation. This finding suggests that, although triacetyloleandomycin has inductive effects on CYP3A, they are countered by a concomitant inhibitory process. Erythromycin is thought to interact via a similar mechanism [42]. Wrighton and Ring [43], using 19-hydroxy midazolam formation as a marker, found that erythromycin itself is a competitive inhibitor of CYP3A catalytic activity in human liver microsomes. (Kronbach et al. [44] have shown that midazolam metabolism is catalyzed by CYP3A4). Jurima-Romet et al. [45] also found erythromycin, as well as clarithromycin and triacetyloleandomycin, to be competitive, reversible inhibitors of CYP3A activity (measured by inhibition of terfenadine metabolism) in human liver microsomes. The relatively low-affinity competitive inhibition of CYP3A activity found does not explain the frequency or magnitude of the interactions that are seen clinically with erythromycin. However, the formation of metabolic–intermediate complexes with CYP3A, which are formed by erythromycin, are much more consistent with the clinical interactions seen with erythromycin. Thus, maximal clinical interaction effects with erythromycin and CYP3A substrates require repeated administration of erythromycin. Induction of CYP3A by macrolide antibiotics may involve both gene activation and stabilization of the enzyme [46]. In rats, triacetyloleandomycin has been shown to be converted to metabolites that tightly bind to the heme moiety of CYP3A, forming a stable complex [47]. Watkins et al. [9] have shown that single doses of triacetyloleandomycin decrease hepatic CYP3A4 activity by 80%, as measured by the erythromycin breath test. Thus, the macrolide antibiotics appear to be interacting by inducing CYP3A and, at the same time, inhibiting CYP3A. Overall, the inhibition is the dominant process. With respect to p-glycoprotein, Gant et al. [48] found that erythromycin increased mdr2 mRNA (expression of which should increase

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biliary p-glycoprotein) in rhesus monkeys. The effect of the macrolides on intestinal p-glycoprotein is unclear. Ketoconazole has been shown to inhibit CYP3A4 in vitro [49] as well as to inhibit p-glycoprotein drug efflux activity [50]. Ketoconazole appears to be a competitive inhibitor of cyclosporine metabolism in human hepatocytes and liver microsomes [51,52]. Jurima-Romet et al. [45] found that ketoconazole, as well as fluconazole and itraconazole, was a competitive, reversible inhibitor of CYP3A metabolism (using terfenadine metabolism as a marker) in human liver microsomes. However, Wrighton and Ring [43], using 19-hydroxy midazolam formation as a marker, found ketoconazole to be a high affinity, non-competitive inhibitor of CYP3A catalytic activity in human liver microsomes. In vitro methodological differences may account for the mechanistic discrepancy. Kurosawa et al. [53] reported that itraconazole may partially reverse multidrug resistance in human leukemia cells. Although not consistent with the other antifungal azoles, clotrimazole has been reported to induce CYP3A in vivo in rat leukocytes [54] and to up-regulate CYP3A4 and p-glycoprotein in a human colon adenocarcinoma cell line and its adriamycin-resistant subline [55]. Ketoconazole and itraconazole appear to inhibit both CYP3A and p-glycoprotein. Fluconazole appears to inhibit CYP3A, but its effect on p-glycoprotein requires further study. Edwards and Bernier [56] reported that grapefruit juice, but not naringin or naringenin (two of its isolated components), inhibits CYP3A activity, as measured by the formation of 6-b-hydroxytestosterone from testosterone in rat liver microsomes. Miniscalco et al. [57] conducted a study evaluating the effects of the flavonoids (naringenin, quercetin and kaempferol) found in grapefruit on the metabolism of (R)-felodipine, (S)-felodipine and nifedipine (CYP3A4 substrates) in human liver microsomes. Quercetin had the greatest inhibitory effect on the rate of metabolism for all three substrates, followed by kaempferol. Naringenin had no inhibitory effect on the rate of metabolism at the lower concentrations (10, 50 and 100 mM), only a mild effect at 300 mM and caused 20–50% inhibition in the rate of metabolism at 500 mM, relative to control values. Induction of P450 cytochromes appear to involve

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activation of gene transcription [58,59]. Rifampin is known to be an inducer of hepatic mixed-function oxidase [60]. It increases CYP3A4 mRNA in cultured duodenal explants [10] and has been found to increase hepatic CYP3A4 activity by an average of 120%, as measured by the erythromycin breath test. Rifampin’s effects can be detected within 48 h of initiation of exposure and returns to within 20% of baseline levels one week after discontinuation [9]. Rifampin has also been found to induce CYP3A4 concentration in human enterocytes by five–eightfold. In addition, the induction was evident within 24 h of initiation of rifampin, increased further over seven days, and returned to baseline within 72 h of discontinuation of rifampin. As also seen in noninduced intestinal biopsies, rifampin-induced CYP3A was only detected in mature enterocytes [11]. Rifampin has been shown to up-regulate p-glycoprotein and CYP3A4 in a human colon adenocarcinoma cell line and its adriamycin-resistant subline [55]. It has also been reported to inhibit p-glycoprotein on multidrug-resistant cells [61]. Thus, although rifampin appears to induce CYP3A4 and p-glycoprotein, its inhibition of p-glycoprotein may decrease all or some of the p-glycoprotein inductive effects. Phenobarbital has been shown to induce CYP3A in vivo in rat leukocytes [54], as well as to increase the microsomal CYP3A content of pre-treated cultured rat hepatocytes [62]. Anecdotal evidence suggests that phenobarbital, phenytoin and dexamethasone induce CYP3A protein in human liver [7,63,64]. The CYP3A inductive effects of phenobarbital and dexamethasone have also been demonstrated in cultured human hepatocytes [65,66]. Schuetz et al. [55] reported that phenobarbital upregulated CYP3A4 and p-glycoprotein in a human colon adenocarcinoma cell line and its adriamycinresistant subline. Thus, phenobarbital also appears to induce p-glycoprotein. Even though the data for these drug interaction mechanisms are limited, most of the information available is consistent with the clinical interactions seen.

9. Cyclosporine drug interactions Many agents have been shown to clinically increase cyclosporine levels (Table 1), potentially

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Table 1 Agents that increase cyclosporine levels Agents

Reference

Amiodarone Ketoconazole Itraconazole Fluconazole Diltiazem Verapamil Nicardipine Methylprednisolone (high dose) Clarithromycin Erythromycin Grapefruit juice Metoclopramide D-a-Tocopheryl polyethylene glycol 1000 succinate (TPGS) a Oral contraceptives and androgens

[67–69] [14,70–74] [75–77] [78–81] [82–86] [86–88] [89] [90]

a

[91,92] [15,93–103] [104] [105] [106] [107,108]

Possible interaction, very limited data.

leading to cyclosporine toxicity. In particular, the anti-fungal azoles, some of the calcium channel blockers and the macrolide antibiotics are of clinical concern, since the potential use of these agents frequently arises due to the immunosuppressive and hypertensive effects of cyclosporine. Wu et al. [1] proposed that although it seems reasonable to assume that with cyclosporine, the effects of inducers on hepatic enzymes approximate the effect on intestinal enzymes, this assumption cannot be applied to enzyme inhibitors (e.g., the effect of an orally administered enzyme inhibitor will be greater on intestinal enzymes than on hepatic enzymes). For the anti-fungal azoles, it appears that ketoconazole causes the greatest increase in cyclosporine levels, followed by itraconazole and then fluconazole. The interaction between ketoconazole and cyclosporine is well established. Gomez et al. [14] found that although ketoconazole caused a significant decrease in cyclosporine clearance in humans (0.3260.09 vs. 0.1860.05 l / h / kg), it was not enough to explain the large increase in bioavailability (22.464.8 vs. 56.4611.7%) that was also seen. This finding is consistent with ketoconazole having a clinically significant effect on intestinal metabolism and / or p-glycoprotein as well as on hepatic metabolism. In vitro data has shown this to be true (i.e. ketoconazole inhibits CYP3A4 [49] and p-glycoprotein drug efflux activity [50]). The calcium channel blockers are a perfect exam-

ple of the fact that drug interactions cannot be automatically categorized by drug class. Although agents, such as verapamil, diltiazem and nicardipine (Table 1), have been shown to clinically increase cyclosporine levels, nifedipine [88] and isradipine [109] do not appear to alter cyclosporine levels. Verapamil [110,111] and diltiazem [110,112] have been shown to inhibit cyclosporine metabolism in human liver microsomes. Christians et al. [113] showed that diltiazem inhibits cyclosporine metabolism in pig small intestinal microsomes. In addition, intestinal metabolite formation rates were altered in human small intestinal microsomes. Verapamil and diltiazem appear not only to inhibit cyclosporine metabolism [110–112], but also to inhibit pglycoprotein activity [34,35,38]. In vivo, diltiazem increased the area under the concentration time curves of cyclosporine and its metabolites in renal allograft recipients [113]. A significant difference was found between male and female patients; however, further work is needed to evaluate gender effects. Clinical studies have established that erythromycin causes dramatic increases in cyclosporine levels. A study by Gupta et al. [15] demonstrated that although erythromycin caused a very mild decrease in cyclosporine clearance (0.3160.16 vs. 0.2760.15 l / h / kg), bioavailability was dramatically increased (36612 vs. 60620%). These results are consistent with erythromycin having a greater effect on pglycoprotein and / or intestinal metabolism than on hepatic metabolism; however, definitive data on the effects on p-glycoprotein are not available. There are also agents that have been shown to clinically decrease cyclosporine levels (Table 2), thus potentially leading to inadequate immunosuppression and allograft rejection in solid organ transplant patients. The potential interactions between anti-seizure medications and anti-tuberculosis Table 2 Agents that decrease cyclosporine levels Agent

Reference

Carbamazepine Phenobarbital Phenytoin Rifampin a Sulphadimidine / trimethoprim

[114] [115] [116,117] [2,118–123] [124]

a

Possible interaction, very limited data.

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agents are clinically important, since cyclosporine can cause seizures and immunosuppression may lead to reactivation of tuberculosis. Rifampin has been shown to significantly increase cyclosporine clearance in humans (0.3060.05 vs. 0.4260.10 l / h / kg), most likely through induction of hepatic metabolism. Of particular interest is that rifampin also causes a decrease in cyclosporine bioavailability (2769 vs. 1063%) to a greater extent than could be explained by the change in hepatic clearance alone [2]. This finding is consistent with rifampin inducing intestinal metabolism and / or p-glycoprotein as well. Rifampin appears to increase CYP3A4 in liver [9] and intestine [10] as well as to up-regulate p-glycoprotein [55].

10. Tacrolimus drug interactions Published information on tacrolimus drug interactions is much more limited than on cyclosporine drug interactions, probably because tacrolimus has been FDA approved for a much shorter period of time. The information available on agents that increase tacrolimus levels is mostly derived from case reports, with the exception of the ketoconazole and fluconazole studies (Table 3). Ketoconazole (200 mg / day) has been found to have very little effect on tacrolimus clearance and, therefore, on hepatic metabolism in humans. However, ketoconazole caused a significant increase in tacrolimus bioavailability (1465 vs. 3068%), findings which suggest a clinically important effect of ketoconazole on intestinal p-glycoprotein and / or intestinal metabolism [3]. These results are consistent with in vitro data for ketoconazole’s effect on CYP3A4 [49] and pglycoprotein drug efflux activity [50]. In vitro, there are a wide range of reported potential drug interactions with tacrolimus in human liver microsomal systems [22,131] and pig small Table 3 Agents that increase tacrolimus levels Agent

Reference

Ketoconazole Fluconazole a Clotrimazole a Danazol Erythromycin

[3] [125] [126] [127] [128–130]

*Possible interaction, very limited data.

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intestinal microsomal systems [22]. Drugs that have been found to inhibit liver microsomal tacrolimus metabolism were found to inhibit small intestinal metabolism as well. Preincubation of human small intestinal microsomes with triacetyloleandomycin and erythromycin significantly inhibited metabolite formation (85 and 80%, respectively) [22]. Triacetyloleandomycin, verapamil and ketoconazole have been shown in vitro to inhibit tacrolimus intestinal metabolite formation in pig gut mucosa with ketoconazole (25 mM), causing the greatest inhibition (80%), followed by verapamil (100 mM, 69%) and triacetyloleandomycin (100 mM, 65%) [23]. To date, there is only one report of an agent that lowers tacrolimus levels in vivo. Rifampin has been reported to decrease tacrolimus levels [130]. Although only a case report, a clinically significant interaction between rifampin and tacrolimus is expected, based on in vitro data [9,10,55], as well as in vivo data with the cyclosporine and rifampin interaction [2]. Dexamethasone, a specific CYP3A inducer, has been shown to increase tacrolimus metabolite formation in rat small intestinal microsomes as compared to untreated rats [22]. Further studies are needed in order to determine the clinical significance and mechanisms.

11. Conclusion Cyclosporine and tacrolimus are metabolized primarily by CYP3A4 in the liver and small intestine. They are also substrates for p-glycoprotein, which acts as a counter-transport pump, actively transporting cyclosporine and tacrolimus back into the intestinal lumen. Traditional teaching has been that hepatic metabolism is of primary importance, and other sites of metabolism play a relatively minor role. However, it appears as though intestinal metabolism plays a much greater role in the pharmacokinetics of orally administered agents than was previously thought. Intestinal metabolism appears to account for as much as 50% of oral cyclosporine metabolism in humans. The quantity of intestinal enzymes, although highly variable, does not appear to be the key to explaining the variability of oral cyclosporine pharmacokinetics in kidney transplant patients. Of more importance is the quantity of intestinal p-glycoprotein, which ac-

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counts for approximately 17% of the variability in oral cyclosporine pharmacokinetics. It may be that p-glycoprotein works to maximize drug exposure to intestinal enzymes, thus decreasing the importance of enzyme quantity. There have been many reports of clinically significant drug interactions with cyclosporine. A similar pattern of clinically significant drug interactions appears to be emerging for tacrolimus. It seems as though compounds that alter (either induce or inhibit) CYP3A4 and / or p-glycoprotein may alter the pharmacokinetics of orally administered cyclosporine and tacrolimus. It should be expected, until further data are available, that the drugs which interact with cyclosporine will also interact with tacrolimus.

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