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Biomedical subjects

L C Rodriguez

Publications and source records attributed to L C Rodriguez.

14 recordsLinked to original sources
PubMed2001

Pharmacokinetics and metabolism of nateglinide in humans.

The pharmacokinetics and metabolism of nateglinide were studied in six healthy male subjects receiving a single oral (120 mg) and intravenous (60 mg) dose of [14C]nateglinide in randomized order. Serial blood and complete urine and feces were collected for 120 h post dose. Nateglinide was rapidly (approximately 90%) absorbed, with peak blood and plasma concentrations at approximately 1 h post dose. The maximal plasma concentrations of radioactivity (6360 ngEq/ml) and nateglinide (5690 ng/ml) were comparable, and plasma radioactivity concentrations were about twice those of blood at all times. Oral bioavailability was 72%, indicating only a modest first-pass effect. After either dose, plasma nateglinide concentrations declined rapidly with elimination half-lives of 1.5 to 1.7 h and plasma clearance of 7.4 l/h. Plasma radioactivity was eliminated more slowly with half-lives of 52 and 35 h in plasma and blood, respectively, after the oral dose. The contribution of this more slowly eliminated component to the AUC(0-infinity) was minor. Nateglinide was extensively metabolized, with excretion predominantly (84-87%) in urine. Only approximately 16% of the dose was excreted unchanged in urine after either dosing route. The major metabolites were the result of oxidative modifications of the isopropyl group. Three of these were monohydroxylated, two of which appeared to be diastereoisomers. Additionally, one metabolite with an unsaturation in the isopropyl group and two diol-containing isomers were identified. Glucuronic acid conjugates resulting from direct glucuronidation of the carboxylic acid were also present. The major metabolite in plasma and urine was the result of hydroxylation of the methine carbon of the isopropyl group.

Administration, Oral↗
PubMed1995

Metabolism of cyclosporin G in the mouse, rat, and dog.

Cyclosporin G (CsG; Sandoz compound OG 37-325) is a cyclic undecapeptide with potent, immunosuppressive activity and is currently in clinical testing for prevention of transplanted solid organ rejection. Although structurally similar to cyclosporin A (CsA), results in animals suggest that CsG has a reduced potential for nephrotoxicity when compared with CsA, while retaining equivalent therapeutic efficacy. In the present study, the major metabolic pathways of CsG in the mouse, rat, and dog were investigated using radiolabeled drug substance to determine if interspecies differences in metabolism exist. The results indicated that the major metabolic pathways in these animal species are similar to those previously reported for CsA, including oxidative modifications at amino acids 1, 4, and 9, and concomitant cyclization of amino acid 1 in two of these metabolites. Moreover, the seven major CsG metabolites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observed in animal excreta and/or blood were identical to those identified in humans. The major circulating metabolite in blood was GM9 (9-hydroxylated CsG) in all species. In addition, numerous unidentified minor metabolites were observed. Renal excretion was a minor elimination pathway, with the majority of drug-related material excreted via the fecal route. In conclusion, CsG was found to proceed through the same metabolic pathways in three animal species and humans, and that species differences in metabolism were primarily because of differences in the relative importance of the pathways observed.

Amino Acid Sequence↗
PubMed1994

Axonal outgrowth within the abnormal scaffold of brain tracts in a zebrafish mutant.

The role of specific axonal tracts for the guidance of growth cones was investigated by examining axonal outgrowth within the abnormal brain tracts of zebrafish cyclops mutants. Normally, the earliest differentiating neurons in the zebrafish brain establish a simple scaffold of axonal tracts. Later-developing axons follow cell-specific pathways within this axonal scaffold. In cyclops embryos, this scaffold is perturbed due to the deletion of some ventromedial neurons that establish parts of the axonal scaffold and the development of an abnormal crease in the brain. In these mutant embryos, the growth cones projected by the neurons of the nucleus of the posterior commissure (nuc PC) are deprived of the two tracts of axons that they sequentially follow to first extend ventrally, then posteriorly. These growth cones respond to the abnormal scaffold in several interesting ways. First, nuc PC growth cones initially always extend ventrally as in wild-type embryos. This suggests that for the first portion of their pathway the axons they normally follow are not required for proper navigation. Second, approximately half of the nuc PC growth cones follow aberrant longitudinal pathways after the first portion of their pathway. This suggests that for the longitudinal portion of the pathway, specific growth cone/axon interactions are important for guiding growth cones. Third, although approximately half of the nuc PC growth cones follow aberrant longitudinal pathways, the rest follow normal pathways despite the absence of the axons that they normally follow. This suggests that cues independent of these axons may be capable of guiding nuc PC growth cones as well. These results suggest that different guidance cues or combinations of cues guide specific growth cones along different portions of their pathway.

Animals↗
PubMed1990

Human biliary metabolites of isotretinoin: identification, quantification, synthesis, and biological activity.

1. The metabolites of isotretinoin (13-cis-retinoic acid, Accutane) were investigated in the bile of two patients with biliary T-tube drainage after administration of a single, oral, 80-mg dose of 14C-isotretinoin. Radioactivity measurements showed that the two patients excreted 22.7 and 17.1% of the dose in their bile in 4 days. 2. The two major drug-related components in the bile were identified as the glucuronide conjugates of 4-oxo-isotretinoin and 16-hydroxy-isotretinoin. Two minor components were identified as the glucuronide conjugates of isotretinoin and 18-hydroxy-isotretinoin. 3. H.p.l.c. analyses of Glusulase-treated bile samples indicated that the glucuronides of isotretinoin and the two major metabolites accounted for about 48% and 44% of the total radioactivity in the bile of the two patients. 4. Racemic 16-hydroxy-isotretinoin was synthesized and evaluated for its effect on human sebocytes in vitro. This metabolite and the other major metabolites of isotretinoin were less active than isotretinoin in inhibiting the proliferation of the sebocytes.

Bile↗
PubMed1987

Quantitative determination of rimantadine in human plasma and urine by GC-MS.

A GC-MS procedure has been developed for the quantitation in plasma and urine of rimantadine, an antiviral drug effective against type A influenza. The assay utilizes selective ion monitoring, methane negative ion chemical ionization (NCI) and stable isotope dilution. Sensitivity to NCI is effected by derivation of rimantadine with pentafluorobenzoyl chloride. The method has been used to quantitate plasma concentrations of rimantadine over a range from 4.2 ng/ml to 416 ng/ml, and urinary concentrations of rimantadine over a range of 21 ng/ml to 2077 ng/ml.

Adamantane↗
PubMed1987

Dose-proportional absorption of etretinate after doses of 25, 50, 75, and 100 mg.

Twelve healthy male subjects received single oral doses of etretinate, ranging from 25 to 100 mg (1 to 4 x 25-mg capsules) in an open-label, four-way randomized crossover design. Plasma concentrations of etretinate and two active metabolites were determined by a specific high-performance liquid chromatographic (HPLC) method. Analysis of variance and orthogonal contrasts were used to assess dose proportionality. Mean (+/- %CV) maximum concentrations after 25- to 100-mg doses were 133 (50), 195 (33), 261 (53), and 446 (65) ng/ml, whereas AUC0-12 values were 581 (46), 1090 (39), 1500 (52), and 2440 (63) ng.hr/ml, respectively. The test for proportionality indicated that Cmax and AUC0-12 increased proportionally with an increase in dose (P greater than 0.05).

Adult↗
PubMed1985

Determination of isotretinoin or etretinate and their major metabolites in human blood by reversed-phase high-performance liquid chromatography.

A method is described for the quantitative analysis of isotretinoin and its 4-oxo metabolite, or of etretinate and its principal metabolites, in human blood in the range 10-2000 ng/ml. Following a simple one-step extraction, the compounds are determined by reversed-phase high-performance liquid chromatography (HPLC) with gradient elution and detection at 365 nm. This highly specific method separates the cis and trans isomers of the parent compounds and their metabolites. Examples are given of the application of this method to clinical studies of these two therapeutically important retinoids.

Journal Article↗
PubMedDate not supplied

Effect of meals on the kinetics of etretinate.

Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

Adult↗
PubMedDate not supplied

Identification of etretinate metabolites in human bile.

The metabolites of etretinate (Tegison) were investigated in bile obtained from two patients with biliary T-tubes. Bile samples were collected for 5 days after administration of a single, oral 100-mg dose of 14C-labeled etretinate. Radioactivity measurements indicated that the two patients excreted 9.6% and 8.0% of the dose in the 5-day bile. The etretinate metabolites in the bile were present mainly as beta-glucuronidase-labile conjugates. HPLC analyses of the beta-glucuronidase-treated bile samples showed no measurable concentrations (less than 10 ng/ml) of etretinate or the 13-cis acid, isoacitretin. Acitretin, the free acid of etretinate, was present and accounted for about 0.9% of the biliary radioactivity. The major portion of the radioactivity in the extracts of the beta-glucuronidase-treated bile samples consisted of two metabolites with shortened side chains. One was identified as the 11, 12-dihydro-13, 14, 15, 20-tetranor phenolic derivative of acitretin, which was previously identified as a human urinary metabolite. The other metabolite was identified as the 11, 12, 13, 14-tetrahydro-15-nor phenolic derivative of acitretin, which has not been previously identified as a metabolite of etretinate.

Adult↗
PubMedDate not supplied

Identification of etretinate metabolites in human blood.

Five metabolites were isolated from the blood of psoriatic patients on chronic therapy with etretinate (Tegison). The two major metabolites were the all-trans acid (acitretin) and the 13-cis acid (isoacitretin), both of which had been previously identified as major metabolites of etretinate in human blood. The other three metabolites had not been previously reported in human blood. One metabolite corresponded to isoacitretin with a hydroxy group on an aromatic methyl group. The other two metabolites had acid side chains shortened by one carbon and a reduced 11, 12-double bond. One of the two metabolites retained the aromatic methoxy group, whereas the other was the phenolic analog.

Biotransformation↗