Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.     

In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia

AIMS: To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species. METHODS: The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds. RESULTS: The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3-6.5% at concentrations < or = 5000 ng ml(-1)) compared to monkey and dog (7.6-19%). Both compounds displayed high binding to human alpha(1)-acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters. CONCLUSION: Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.     

Disposition of imatinib and its metabolite CGP74588 in a patient with chronic myelogenous leukemia and short-bowel syndrome

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by means of cytochrome P450 3A and excreted primarily in the bile. Although the bioavailability of imatinib mesylate is more than 97%, the exact gastrointestinal site of its absorption is unknown. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP74588 in the plasma and jejunostomy output of a patient with newly diagnosed chronic myelogenous leukemia. She had previously lost most of her small bowel and all of her colon as a result of mesenteric artery thrombosis and radiation-induced colitis and/or proctitis. Imatinib pharmacokinetics in plasma indicated that approximately 20% of the patient's 400-mg dose was absorbed. The jejunostomy output contained 338 mg of imatinib, which was consistent with 320 mg of a nonabsorbed dose plus approximately 23% of the absorbed dose being excreted unchanged in the bile. These data indicate the importance of considering gastrointestinal anatomic abnormalities or disease states when oral imatinib is dosed.     

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

AIMS

Imatinib mesylate (Gleevec®/Glivec®), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently co-administered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics.

METHODS

Twelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec®) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite {"type":"entrez-protein","attrs":{"text":"CGP74588","term_id":"875877231"}}CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally.

RESULTS

PPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 µg ml⁻¹ h alone vs 33.1 µg ml⁻¹ h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (C_max) (2.04 µg ml⁻¹ alone vs 2.02 µg ml⁻¹ with omeprazole, P= 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P= 0.13).

CONCLUSIONS

Our results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and C_max two-fold.     

Clinical pharmacokinetics of imatinib

Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100 mg, 400 mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 +/- 0.8 microg/mL at peak and 1.2 +/- 0.8 microg/mL at trough, exceeding the 0.5 microg/mL (1 micromol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and alpha1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18-70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.     

The influence of food on the pharmacokinetics of CGP 6140 (amocarzine) after oral administration of a 1200 mg single dose to patients with onchocerciasis.

Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N-oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/- s.d.) AUC CGP 6140 values were 67.0 +/- 10.8 mumol l-1 h in fed and 22.0 +/- 17.2 mumol l-1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/- s.d. were 12.7 +/- 2.8 mumol l-1 in fed and 4.7 +/- 4.1 mumol l-1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/- s.d.) AUC of the N-oxide metabolite was 59.9 +/- 10.7 mumol l-1 h in fed and 23.4 +/- 16.2 mumol l-1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/- 11.5 and 11.4 +/- 8.0% of the dose for the N-oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N-oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.     

Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride

The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [(14)C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (～240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (～679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (～31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (～19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (～17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed.     

Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite

A method is described for the simultaneous determination of the carboxylic acid and N-acetyl-derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/- 23.5 ng/ml at 3 +/- 1 h, followed by an elimination half-life of 7.1 +/- 1.6 h, systemic clearance of 21.1 +/- 7.1 l/h, volume of distribution of 205 +/- 371 and cumulative urinary excretion of 1.3 +/- 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/- 307 ng/ml at 7 +/- 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N-acetyl primaquine was not detected in plasma or urine. Following [14C]-primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]-radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N- acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.     

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantification of the anti-leukemia drug STI571 (Gleevec) and its metabolite (CGP 74588) in monkey plasma using a semi-automated solid phase extraction procedure and liquid chromatography-tandem mass spectrometry

Signal Transduction Inhibitor 571 (STI571, formerly known as CGP 57148B) or Gleevec™ received fast track approval by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML). STI571 (Gleevec™) is a revolutionary and promising new oral therapy for CML, which functions at the molecular level with high specificity. The dramatic improvement in efficacy compared with existing treatments prompted an equally profound increase in the pace of development of Gleevec™. The duration from first dose in man to completion of the New Drug Application (NDA) filing was less than 3 years. In addition, recently, FDA approved Gleevec™ for the treatment of gastrointestinal stromal tumor (GIST). In order to support all toxicokinetic (TK) studies with sufficient speed to meet various target dates, a semi-automated procedure using solid phase extraction (SPE) was developed and validated. A Packard Multi-Probe I and a SPE step in a 96-well plate format were utilized. A 3M Empore octyl (C₈)-standard density 96-well plate was used for plasma sample extraction. A Sciex API 3000 triple quadrupole mass spectrometer with an atmospheric pressure chemical ionization (APCI) interface operated in positive ion mode was used for detection. Lower limits of quantification of 1.00 and 2.00 ng/ml were attained for STI571 and its metabolite, CGP 74588, respectively. The method proved to be rugged and allowed the simultaneous quantification of STI571 and CGP 74588 in monkey plasma. Herein, assay development, validation, and representative concentration–time profiles obtained from TK studies are presented.     

Stability-indicating HPTLC determination of imatinib mesylate in bulk drug and pharmaceutical dosage form

A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of imatinib mesylate both as a bulk drug and in formulations was developed and validated. The method employed HPTLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform:methanol (6:4, v/v). The system was found to give compact spot for imatinib mesylate (R(f) value of 0.53+/-0.02). Densitometric analysis of imatinib mesylate was carried out in the absorbance mode at 276 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r(2)=0.9966+/-0.0013 with respect to peak area in the concentration range 100-1000 ng per spot. The mean value+/-S.D. of slope and intercept were 164.85+/-0.72 and 1168.3+/-8.26 with respect to peak area. The method was validated for precision, recovery and robustness. The limits of detection and quantitation were 10 and 30 ng per spot, respectively. Imatinib mesylate was subjected to acid and alkali hydrolysis, oxidation and thermal degradation. The drug undergoes degradation under acidic, basic, oxidation and heat conditions. This indicates that the drug is susceptible to acid, base hydrolysis, oxidation and heat. Statistical analysis proves that the method is repeatable, selective and accurate for the estimation of said drug. The proposed developed HPTLC method can be applied for identification and quantitative determination of imatinib mesylate in bulk drug and dosage forms.     

Imatinib mesylate (STI571; Glivec)--a new approach in the treatment of biliary tract cancer?

Non-resectable biliary tract cancer is associated with poor prognosis due to widespread resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to explore new therapeutic approaches like the inhibition of tyrosine kinases. The aim of this study was to determine the expression of c-kit and platelet-derived growth factor (PDGF) receptors (PDGFRs) and the effects of the tyrosine kinase inhibitor imatinib +/- 5-fluorouracil (5-FU) on proliferation and apoptosis in biliary tract cancer cell lines. The expression of c-kit and PDGFR mRNA was examined in 12 biliary tract cancer cell lines using RT-PCR. Cells were treated with imatinib (1, 10, 20 and 50 micromol/l) +/- 5-FU (0.1 microg/ml) for 6 days and inhibition of cell growth was assessed by manual cell counting. Cell proliferation and apoptosis were analyzed by flow cytometry of BrdU and Annexin-V/propidium iodide-stained cells. c-kit and PDGF mRNA expression was detected in 50 and 75%, respectively. Imatinib (10 and 20 micromol/l) alone inhibited cell growth significantly higher in c-kit+ cell lines (p<0.02) and inhibition was independent of PDGFR status. The combination with 5-FU increased the effect of imatinib mesylate in all cell lines. Treatment of cells with imatinib +/- 5-FU was associated with a significant induction of apoptosis, but no inhibition of proliferation. We conclude that imatinib alone exerts marked effects on c-kit+ biliary tract cancer cell lines only at intermediate and high concentrations, but there is a potential role of low-dose imatinib in combination with 5-FU for the treatment of biliary tract cancers.     

LC-MS-MS analysis of 2-pyridylacetic acid, a major metabolite of betahistine: application to a pharmacokinetic study in healthy volunteers

1. A sensitive liquid chromatographic-tandem mas spectrometric assay was developed and validated to determine the major metabolite of betahistine, 2-pyridylacetic acid, in human plasma. 2. The analyte was extracted from plasma samples by liquid-liquid extraction and analysed using liquid chromatography-tandem mass spectrometry with an electrospray ionization interface. The method has a lower limit of quantitation of 1 ng ml(-1) fir a 0.5-ml plasma aliquot. The intra- and interday precision (relative standard deviation), calculated from quality control (QC) samples, was less than 10%. Accuracy as determined from QC samples was within +/-7%. 3. The validated method was successfully applied to a pharmacokinetic study of betahistine in healthy volunteers. After oral administration of a single dose of 24 mg betahistine mesylate to 20 healthy Chinese male volunteers, Cmax was 339.4 ng ml(-1) (range 77.3-776.4 ng ml(-1)). The t(1/2) was 5.2 h (range 2.0(-1)-11.4h). The AUC(0-t) obtained was 1153.5 ng ml(-1) h (range 278.5-3150.8 ng ml(-1)). The disposition of the metabolite exhibited a marked interindividual variation. 4. The plasma concentrations of the parent drug were less than 0.5 ng ml(-1), suggesting that it undergoes almost complete first-pass metabolism. The reported two active metabolites were not detected in the plasma of any volunteer. Although there is no evidence that the major metabolite has pharmacological activity, the clinical importance of 2-pyridylacetic acid in humans should be reinvestigated.     

Renal dysfunction in a renal transplant patient treated concurrently with cyclosporine and imatinib

Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72?year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400?mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123?μmol/L to 196?μmol/L and an elevation in whole blood cyclosporine concentrations from 79?μg/L to 139?μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150-186?μmol/L) and cyclosporine concentrations (53-97?μg/L). A prolonged partial response to therapy for 19?months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1?ng/ml and 139?ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration.     

Reduced exposure of imatinib after coadministration with acetaminophen in mice

Purpose:

Imatinib is an efficacious drug against chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) due to selective inhibition of c-KIT and BCR-ABL kinases. It presents almost complete bioavailability, is eliminated via P450-mediated metabolism and is well tolerated. However, a few severe drug-drug interactions have been reported in cancer patients taking acetaminophen.

Materials and Methods:

Male ICR mice were given 100 mg/kg single dose of imatinib orally or imatinib 100 mg/kg (orally) coadministered with acetaminophen intraperitoneally (700 mg/kg). Mice were euthanized at predetermined time points, blood samples collected, and imatinib plasma concentration measured by HPLC.

Results:

Imatinib AUC_0-12 was 27.04 ± 0.38 mg·h/ml, C_max was 7.21 ± 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC_0-12 and C_max decreased 56% and 59%, respectively and a longer half-life was observed (5.6 hours).

Conclusions:

The study shows a pharmacokinetic interaction between acetaminophen and imatinib which may render further human studies necessary if both drugs are administered concurrently to cancer patients.     

The disposition of pyrimethamine in the isolated perfused rat liver

We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 microCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1/2) of 3.0 +/- 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0----infinity was 6.9 +/- 1.9 microgram/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 +/- 25.3 ml/hr identical to 8.6% of liver perfusate flow) with a large volume of distribution (267.5 +/- 55.3 ml) in the IPRL. The combined AUCS(0----5hr) for pyrimethamine (AUC 4.8 +/- 0.5 microgram/hr/ml) and pyrimethamine 3-N-oxide (AUC0----5hr 0.9 +/- 0.6 microgram/hr/ml) accounted for 57% of the total AUC0----5hr of [14C] radioactivity (10.0 +/- 2.6 micrograms/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 +/- 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 +/- 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 +/- 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 +/- 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.     

Imatinib mesylate in the treatment of gastrointestinal stromal tumour

Imatinib mesylate is a selective and potent small-molecule inhibitor of tyrosine kinases, including Kit, platelet-derived growth factor receptor, and the BCR-Abl fusion protein. Kit plays an important role in gastrointestinal stromal tumours (GISTs) and is one of the most exciting therapeutic targets discovered so far. Clinical trials have consistently shown the dramatic efficacy of imatinib mesylate in patients with GIST. This article will review the development and pharmacology of this small-molecule inhibitor and summarise the clinical trials of imatinib mesylate for the treatment of GIST. Although imatinib mesylate has significantly improved the outcomes of most patients with advanced GIST, unanswered questions remain: what is the role of imatinib mesylate in the pre- and postoperative settings? What is the mechanism of the antitumour activity of imatinib? How do you manage patients whose tumours are refractory to imatinib mesylate?     

Current status of unoprostone for the management of glaucoma and the future of its use in the treatment of retinal disease

Imatinib mesylate is a selective and potent small-molecule inhibitor of tyrosine kinases, including Kit, platelet-derived growth factor receptor, and the BCR–Abl fusion protein. Kit plays an important role in gastrointestinal stromal tumours (GISTs) and is one of the most exciting therapeutic targets discovered so far. Clinical trials have consistently shown the dramatic efficacy of imatinib mesylate in patients with GIST. This article will review the development and pharmacology of this small-molecule inhibitor and summarise the clinical trials of imatinib mesylate for the treatment of GIST. Although imatinib mesylate has significantly improved the outcomes of most patients with advanced GIST, unanswered questions remain: what is the role of imatinib mesylate in the pre- and postoperative settings? What is the mechanism of the antitumour activity of imatinib? How do you manage patients whose tumours are refractory to imatinib mesylate?