ABSTRACT
OBJECTIVES: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. METHODS: Patients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin). RESULTS: Mean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). CONCLUSIONS: Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk. TRIAL REGISTRY AND NUMBER: ClinicalTrials.gov, NCT01075984.
Subject(s)
Antifungal Agents/adverse effects , Antifungal Agents/pharmacokinetics , Chemoprevention/adverse effects , Chemoprevention/methods , Invasive Fungal Infections/prevention & control , Triazoles/adverse effects , Triazoles/pharmacokinetics , Administration, Intravenous , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antifungal Agents/administration & dosage , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Immunocompromised Host , Leukemia, Myeloid, Acute/complications , Male , Middle Aged , Myelodysplastic Syndromes/complications , Triazoles/administration & dosage , Young AdultABSTRACT
The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was â¼90%, with â¼50% appearing in urine and â¼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.
Subject(s)
Antipsychotic Agents/metabolism , Glucuronides/analysis , Heterocyclic Compounds, 4 or More Rings/metabolism , Adult , Antipsychotic Agents/blood , Antipsychotic Agents/chemistry , Antipsychotic Agents/urine , Area Under Curve , Dibenzocycloheptenes , Glucuronides/metabolism , Heterocyclic Compounds, 4 or More Rings/blood , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/urine , Humans , Hydroxylation , Male , Middle Aged , Radioligand Assay , Young AdultABSTRACT
Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.
Subject(s)
Bile/metabolism , Feces/chemistry , Norpregnenes/pharmacokinetics , Ovariectomy , Selective Estrogen Receptor Modulators/pharmacokinetics , Administration, Oral , Animals , Biotransformation , Chromatography, High Pressure Liquid , Drug Administration Schedule , Female , Gas Chromatography-Mass Spectrometry , Macaca fascicularis , Norpregnenes/administration & dosage , Norpregnenes/blood , Norpregnenes/urine , Reproducibility of Results , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/blood , Selective Estrogen Receptor Modulators/urine , Sulfates/pharmacokinetics , Tandem Mass SpectrometryABSTRACT
Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.
Subject(s)
Norpregnenes/pharmacokinetics , Ovariectomy , Selective Estrogen Receptor Modulators/pharmacokinetics , Administration, Oral , Animals , Biotransformation , Brain/metabolism , Breast/metabolism , Chromatography, High Pressure Liquid , Drug Administration Schedule , Female , Gas Chromatography-Mass Spectrometry , Macaca fascicularis , Molecular Structure , Norpregnenes/administration & dosage , Norpregnenes/blood , Norpregnenes/chemistry , Reproducibility of Results , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/blood , Selective Estrogen Receptor Modulators/chemistry , Sulfates/pharmacokinetics , Tandem Mass Spectrometry , Tissue Distribution , Uterus/metabolism , Vagina/metabolismSubject(s)
Flavonoids/chemistry , Indolequinones , Quercetin/analogs & derivatives , Quinones/chemistry , Benzoquinones/chemistry , Benzoquinones/pharmacology , Flavonoids/pharmacology , Flavonols , Glutathione , HL-60 Cells , Humans , Indoles/chemistry , Luteolin , Molecular Structure , Mutagens , Oxidants/chemistry , Oxidants/pharmacology , Quercetin/chemistry , Quercetin/pharmacology , Quinones/pharmacology , Salmonella typhimurium/drug effects , Structure-Activity RelationshipABSTRACT
The fact that dietary compounds influence the susceptibility of human beings to cancer, is widely accepted. One of the possible mechanisms that is responsible for these (anti)carcinogenic effects is that dietary constituents may modulate biotransformation enzymes, thereby affecting the (anti)carcinogenic potential of other compounds. This ambiguous theme is the basis for the present paper. The possible effects of enzymatic bioactivation and detoxification of dietary constituents are discussed using two representative examples of phase I and phase II biotransformation enzymes i.e., cytochrome P450 and glutathione S-transferase. Furthermore, the impact of genetic polymorphisms of these two enzyme systems is considered. Although it is very difficult on the basis of the enzyme inducing or inhibiting properties of dietary compounds, especially to characterize them as anticarcinogenic, for certain constituents it is acknowledged that they have anticarcinogenic properties. As such, this provides for an important mechanistic substantiation of the established cancer chemopreventive effect of a diet rich in fruits and vegetables.
Subject(s)
Biotransformation , Carcinogens/toxicity , Diet , Neoplasms/prevention & control , Carcinogens/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Gene Expression Regulation, Neoplastic , Genetic Variation , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Humans , Kinetics , Xenobiotics/pharmacokineticsABSTRACT
The cyclopentenone prostaglandin A2 (PGA2) is known to inhibit cell proliferation, and metabolism of this compound thus might be important in controlling its ultimate function. The glutathione-related metabolism of PGA2 was therefore investigated both with purified glutathione S-transferase P1-1 (GSTP1-1) and with IGR-39 human melanoma cells. Firstly, the irreversible inhibition of human GSTP1-1 and its mutants C47S, C101S, and C47S/C101S was studied. PGA2 appeared to inhibit GSTP1-1 mainly by binding to the cysteine 47 moiety of the enzyme. This binding was reversed by a molar excess of GSH, indicating that retro-Michael cleavage occurs. Secondly, after exposing IGR-39 human melanoma cells to PGA2, both diastereoisomers of the PGA2-glutathione conjugate are excreted into the medium, although with a clear excess of the S-form, due to its preferential formation by the GSTP1-1 present in the cells. Thirdly, the effect of PGA2 on intracellular GST activity was determined by quantification of the excreted glutathione conjugate S-(2,4-dinitrophenyl)glutathione (DNPSG) after exposure to 1-chloro-2,4-dinitrobenzene. DNPSG excretion was inhibited after incubation with 10 or 20 microM PGA2 for 1 or 4 hr, as a result of glutathione depletion, reversible GST inhibition, and covalent modification of intracellular GST. Furthermore, PGA2 also inhibited transport of DNPSG by the multidrug resistance-associated protein, an effect that was reversible and competitive. In conclusion, PGA2 modulates all three aspects of the glutathione-mediated biotransformation system, i.e. GSH levels, GSTP1-1 activity, and transport of GSH conjugates. A role for GSTP1-1 as a specific transport protein inside the cell is indicated.
Subject(s)
Glutathione/metabolism , Prostaglandins A/metabolism , Biotransformation , Glutathione S-Transferase pi , Glutathione Transferase/antagonists & inhibitors , Glutathione Transferase/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Melanoma , Tumor Cells, CulturedABSTRACT
Using 1H NMR two diastereoisomers of the ethacrynic acid glutathione conjugate (EASG) as well as ethacrynic acid (EA) could be distinguished and quantified individually. Chemically prepared EASG consists of equal amounts of both diastereoisomers. GSTP1-1 stereospecifically catalyzes formation of one of the diastereoisomers (A). The GSTP1-1 mutant C47S and GSTA1-1 preferentially form the same diastereoisomer of EASG as GSTP1-1. Glutathione conjugation of EA by GSTA1-2 and GSTA2-2 is not stereoselective. When human melanoma cells, expressing GSTP1-1, were exposed to ethacrynic acid, diastereoisomer A was the principal conjugate formed, indicating that even at physiological pH the enzyme catalyzed reaction dominates over the chemical conjugation.
Subject(s)
Ethacrynic Acid/metabolism , Glutathione Transferase/metabolism , Glutathione/metabolism , Isoenzymes/metabolism , Amino Acid Substitution , Glutathione Transferase/chemistry , Humans , Isoenzymes/chemistry , Melanoma/enzymology , Point Mutation , Stereoisomerism , Substrate Specificity , Tumor Cells, CulturedABSTRACT
In the present study the irreversible inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by alpha, beta-unsaturated aldehydes and ketones was studied. When GSTP1-1 was incubated with a 50-fold molar excess of the aldehydes acrolein (ACR) and 4-hydroxy-2-nonenal (HNE) and the ketones curcumin (CUR) and ethacrynic acid (EA) at 22 degrees C, all of them inactivated GSTP1-1. The remaining activity after 4 h of incubation in all cases was lower than 10%. The aldehydes crotonaldehyde (CRA), cinnamaldehyde (CA) and trans-2-hexenal were found to inhibit GSTP1-1 only at a 5000-fold molar excess and even then, for example, for CA a higher remaining activity of 17% was observed. The same inhibition experiments were conducted with 3 mutants of GSTP1-1: the C47S and C101S mutants and the double mutant C47S/C101S. Remaining activity for C47S varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. For C101S it varied between 0 and 9% and for the double mutant C47S/C101S, activity after 4 h of incubation was variable. Again it varied between +/- 40% for CRA, CA, CUR and HEX and +/- 80% for ACR, EA and HNE. EA is known to react almost exclusively with cysteine 47. When [14C]EA was incubated with the GSTP1-1, modified by the alpha, beta-unsaturated carbonyl compounds, no [14C]EA was incorporated in the enzyme, indicating that in all cases this cysteine residue was one of the major targets. Since Michael addition with these reagents is known to be reversible, the results of incubation of the inactivated enzymes with an excess of glutathione (GSH) were determined. For all compounds, a restoration of the catalytic activity was observed. The results indicate that alpha, beta-unsaturated carbonyl derivatives inhibit GSTP1-1 irreversibly mainly by binding to cysteine residues of GSTP1-1, especially Cys-47, This means that some of these compounds (e.g. CUR) might modify GST activity in vivo when GSH concentrations are low by covalent binding to the enzyme.
Subject(s)
Aldehydes/pharmacology , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Ethacrynic Acid/pharmacology , Glutathione Transferase/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Ketones/pharmacology , Acrolein/analogs & derivatives , Acrolein/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Glutathione S-Transferase pi , Glutathione Transferase/metabolism , Humans , Isoenzymes/metabolism , Mutagenesis, Site-Directed/geneticsABSTRACT
The glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene in intact human IGR-39 melanoma cells was determined by the quantification by HPLC-analysis of the excreted glutathione (GSH) conjugate (S-(2,4-dinitrophenyl)glutathione; DNPSG). The major GST subunit expressed in these melanoma cells is the pi-class GST subunit P1. Using this system, the effect of exposure for 1 h to a series of alpha, beta-unsaturated carbonyl compounds at non-toxic concentrations was studied. Curcumin was the most potent inhibitor (96% inhibition at 25 microM), while 67 and 61% inhibition at 25 microM was observed for ethacrynic acid and trans-2-hexenal, respectively. Moderate inhibition was observed for cinnamaldehyde and crotonaldehyde, while no inhibition was found for citral. The reactive acrolein did not inhibit the DNPSG-excretion at 2.5 microM, the highest non-toxic concentration. Up to about 50% GSH-depletion was found after treatment with crotonaldehyde, curcumin and ethacrynic acid, however the consequences for GST conjugation are presumably small. Reversible inhibition of GST was the major mechanism of inhibition of DNPSG-excretion in melanoma cells, except in the cases of curcumin and ethacrynic acid, which compounds also inactivated GSTP1-1 by covalent modification. This was clear from the fact that depending on the dose between 30 and 80% inhibition was still observed after lysis of the cells, under which conditions reversible inhibition was is absent. Intracellular levels of DNPSG remained relatively high in the case of ethacrynic acid. It is possible that ethacrynic acid also inhibits the transport of DNPSG by inhibition of the multidrug resistance-associated protein gene encoding glutathione conjugate export pump (MRP/GS-X pump) in some way.
Subject(s)
Aldehydes/pharmacology , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Ethacrynic Acid/pharmacology , Glutathione Transferase/antagonists & inhibitors , Melanoma/enzymology , Monoterpenes , Skin Neoplasms/enzymology , Terpenes/pharmacology , Acrolein/analogs & derivatives , Acrolein/pharmacology , Acyclic Monoterpenes , Chromatography, High Pressure Liquid/methods , Glutathione/analysis , Humans , Tumor Cells, CulturedABSTRACT
The drug disulfiram (DSF, Antabuse) has been used in the therapy of alcohol abuse. It is a potent inhibitor of aldehyde dehydrogenase. Its reduced form, diethyldithiocarbamate (DDTC), and further metabolites show similar activities. DSF and DDTC have also been widely used to inhibit mixed-function oxidases. In this study, the reversible inhibition and time-dependent inactivation of the major rat and human glutathione S-transferase (GST) isoenzymes by DSF and DDTC was investigated. Reversible inhibition, using 1-chloro-2,4-dinitrobenzene as substrate for the GST alpha-, mu-, and pi-class, expressed as I50 (in microM), ranged from 5-18 (human A1-1), 43-57 (rat 4-4) and 66-83 (rat 1-1), for both DSF and DDTC. The I50 for rat GST theta, using 1,2-epoxy-3-(p-nitrophenoxy)-propane as substrate, was 350 microM for DDTC. The other GSTs were significantly less sensitive to inhibition. The major part of reversible inhibition by DSF was shown to be due to DDTC, formed rapidly upon reduction of DSF by the glutathione (GSH) present in the assay to measure GST activity. The oxidized GSH formed upon reduction of DSF might also have made a minor contribution to reversible inhibition. The rat and human pi-class was, by far, the most sensitive class for time-dependent inactivation by DSF, but no such inactivation was observed for any of the GSTs by DDTC. Moderate susceptibility to inactivation by DSF of all the other GSTs was observed, except for human A2-2, which does not possess a cysteine residue. Consistent with the assumption that a thiol residue is involved in this inactivation, a significant part of the activity could be restored by treatment of the inactivated GST with GSH or dithiotreitol.
Subject(s)
Disulfiram/pharmacology , Ditiocarb/pharmacology , Glutathione Transferase/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Animals , Dithiothreitol/pharmacology , Glutathione/pharmacology , Glutathione Transferase/isolation & purification , Humans , Isoenzymes/isolation & purification , Rats , Spectrophotometry, Ultraviolet , Time FactorsABSTRACT
1. The metabolism of 50 microM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile. 2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7-dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl-acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins. 3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively. 4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed. 5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes. 6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes.
Subject(s)
Coumarins/metabolism , Microsomes, Liver/metabolism , Biotransformation , Blotting, Western , Coumarins/pharmacokinetics , Cytochrome P-450 Enzyme System/analysis , Cytochrome P-450 Enzyme System/metabolism , Humans , In Vitro Techniques , Isoenzymes/analysis , Isoenzymes/metabolism , Microsomes, Liver/enzymology , Umbelliferones/metabolismABSTRACT
Dietary factors have been shown to affect excretion of fecapentaenes, potent mutagens present in human feces. Apart from effects of the diet on the bacterial synthesis of fecapentaenes in the bowel, fecapentaene excretion is likely to be indirectly influenced by the composition of the bowel contents, in particular fecapentaene-binding or -solubilizing factors. In the present study, interactions between dietary fiber and fecapentaene-12 (FP-12), as well as the effects of bile acids and calcium on the solubility of FP-12 in aqueous solutions, have been investigated in vitro. The results demonstrated that FP-12 may strongly adsorb to fiber, as indicated by reduced concentrations in the aqueous PBS phase when increasing amounts of fiber are added. This fecapentaene-binding capacity of fiber may explain the positive correlations that have previously been found between excreted fecapentaene concentrations and fiber consumption in human population studies. Further, it was found that at concentrations physiologically occurring in feces, both cholic and deoxycholic acid as well as mixtures of bile acids may increase the aqueous solubility of FP-12. This solubilizing effect of bile acids can be reduced by adding calcium at physiological concentrations of 2.5 mg/ml. It is hypothesized that high dietary fiber intake may increase fecapentaene excretion as a result of this fecapentaene fiber adsorption, which in turn may result in diminished exposure of the human bowel epithelium to these putative initiators of colorectal cancer. In contrast, high concentrations of fecal bile acids may act as fecapentaene-solubilizing factors which increase fecapentaene bioavailability, thereby possibly resulting in increased risk for colorectal cancer.