Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat: evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques.

Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-(14)C]rofecoxib to intact rats, the plasma C(max) (at approximately 1 h) was followed by a secondary C(max) (at approximately 10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-(14)C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary C(max) for rofecoxib was observed (at approximately 10 h), which occurred only in the intact animals. These results indicate that reversible metabolism of rofecoxib to 5-hydroxyrofecoxib occurs in the rat and that the process is dependent upon an uninterrupted bile flow. Studies on the contents of the gastrointestinal tract of rats showed that conversion of 5-hydroxyrofecoxib to parent compound occurs largely in the lower intestine. Treatment of rats with [5-(18)O]5-hydroxyrofecoxib, followed by liquid chromatography-tandem mass spectrometry analyses of plasma samples, confirmed that 5-hydroxyrofecoxib undergoes metabolism to the parent drug, yielding [1-(18)O]rofecoxib, [2-(18)O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-(18)O(2)]rofecoxib afforded the same three isotopic variants of rofecoxib. These findings are consistent with a metabolic sequence involving 5-hydroxylation of rofecoxib, biliary elimination of the corresponding glucuronide, and deconjugation of the glucuronide in the lower gastrointestinal tract. Reduction of the 5-hydroxyrofecoxib thus liberated yields a hydroxyacid that cyclizes spontaneously to regenerate rofecoxib, which is reabsorbed and enters the systemic circulation. This sequence represents a novel form of enterohepatic recycling and reflects the susceptibility of 5-hydroxyrofecoxib, as well as rofecoxib itself, to reversible 2-furanone ring opening under in vivo conditions.

The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).

A receptor in pituitary and hypothalamus that functions in growth hormone release.

Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.

Cytogenetic abnormalities in colon cancer patients: a comparison of T- and B-lymphocytes.

Cytogenetic analysis of peripheral blood lymphocytes of 19 colorectal cancer patients was carried out in short term blood cultures (T-cells) as well as in Epstein-Barr virus transformed B-cell lymphoblastoid cell lines. One hundred Giemsa-banded metaphases from the T lymphocytes and 50 metaphases from the B lymphocytes of each patient were evaluated for cytogenetic abnormalities. Clonality was not observed in every paired sample. Structural and/or numerical aberrations were most frequent in chromosomes #1, #2, #5, #7, #9, #12, #14, #17, #18 and #21. Aberrations among these chromosomes could be observed individually in either of the cultures, which proves that the analysis of both cultures (T and B cells) is complementary to each other. In some cases involving multiple primary cancers it was interesting that the specific chromosomal change, crucial for a particular malignancy, was identified only in the lymphoblastoid cell line analysis. This supports the notion that B-cell analysis can serve as a useful adjunct to the study of short-term blood cultures and also poses a question as to whether the specific chromosomal changes observed in the analysis are confined to the B-cell lineage.

Chromosome anomalies in human breast cancer: evidence for specific involvement of 1q region in lymphocyte cultures.

Constitutional chromosome abnormalities that may predispose a group of individuals to develop certain neoplasms have been reported for some human solid tumors. Deletions of 13q in retinoblastoma, 11p in Wilms' tumor, 1p in neuroblastoma, 3p in renal cell carcinoma, 5q in colorectal carcinoma and 22q in meningioma are examples of such anomalies. In breast carcinoma, a specific cytogenetic defect has not been conclusively identified. We have studied Phytohemagglutinin-stimulated lymphocytes of 76 breast cancer patients, 68 predisposed family members, 40 controls, and 30 additional controls with lung cancer to determine whether nonrandom chromosome defects are present. From each sample 100, G-or Q-banded metaphase spreads were studied for rearrangements. A marked clustering of alterations in the long arm of chromosome no. 1 (q11-22) was seen in breast cancer patients and in some predisposed family members. Alterations in 1q were present in 1% to 3% of metaphases, and included translocations to chromosomes 3, 6, 7, 9, 12, 15, 17, 18, 21 and the X; deletion of 1q, or pericentric inversion. Twelve out of 62 (19.3%) familial cases, 3 out of 14 (21.4%) sporadic cases, 9 out of 68 (13.2%) predisposed cases and 2 out of 40 (5%) control cases showed 1q alterations. None of the 30 lung cancer patients showed chromosome 1 anomaly in this region. This is consistent with the reports on primary breast tumor tissues, cell lines and pleural effusions where 1q defects have been reported. We conclude that chromosome 1q rearrangement might be one of the primary lesions specifically associated with the development of breast cancer.

Disseminated Mycobacterium chelonei infection following cadaveric renal transplantation: favorable response to cefoxitin.

This article describes a case of disseminated Mycobacterium chelonei infection in a renal transplant recipient. This patient, who underwent thoracic duct drainage prior to cadaveric renal transplantation, developed M chelonei bacteremia and numerous subcutaneous nodules a few weeks after transplantation. The M chelonei initially responded to amikacin and tetracycline. Because of side effects and bacterial resistance, however, these drugs had to be discontinued. Subsequent treatment with cefoxitin led to reduction in size of subcutaneous nodules, but control of the infection was not achieved until an intravascular nidus of infection at the anastomotic site of an arteriovenous fistula was removed.