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Biomedical subjects

S H Chiu

Publications and source records attributed to S H Chiu.

At least 55 records · Page 3Linked to original sources
PubMed1987

Number of melanocytic nevi as a major risk factor for malignant melanoma.

A study of 121 melanoma patients and 139 control subjects from the University of California, San Francisco clinics was conducted among whites to examine the relationship between number of melanocytic nevi and cutaneous melanoma. Nevi that measured 2 mm or more in diameter were counted over the body by a dermatologist and a dermatology fellow. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p less than 0.001). Relative risks were 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for more than 100 nondysplastic melanocytic nevi. Relative risks were 3.8 (p = 0.001) for 1 to 5 dysplastic nevi and 6.3 (p = 0.003) for 6 or more of these lesions. Report of blistering sunburns or of a previous skin cancer and having red or blond hair at the age of 20 were also independently associated with an increased risk of cutaneous melanoma. If confirmed in larger studies, the results presented on number of nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma.

Dysplastic Nevus Syndrome↗
PubMed1984

Biosynthesis of the glycocinnamoylspermidine antibiotic, cinodine.

The biosynthesis of cinodine from a combination of 14C- and 13C-labeled precursors has been investigated. Tyrosine was shown to be incorporated efficiently into the cinnamoyl moiety and glucosamine was found to be the origin of the three carbohydrate moieties. The relationship between the substrate dose and the enrichment of the labeled antibiotic has been elucidated so that it is possible to predict both the specific activity and the yield of the antibiotic obtained from the labeled substrates.

Aminoglycosides↗
PubMedDate not supplied

The role of drug metabolism in drug discovery: a case study in the selection of an oxytocin receptor antagonist for development.

Drug discovery is a process involving multiple disciplines and interests. During the research phase of drug discovery, usually a large number of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect to pharmacodynamics, pharmacokinetics, and toxicity are commonly encountered at this stage. Drug metabolism, as a discipline participating in a drug discovery team, can play an important role in identifying factors underlying the problems, facilitate the optimal selection of compounds for further development, provide information on metabolites for possible improvement in drug design, and contribute to the identification of the appropriate animal species for subsequent toxicity testing. During the process of evaluating oxytocin receptor antagonists for further development for treatment of preterm labor, in vivo and in vitro drug metabolism studies conducted in rats, dogs, and monkeys contributed to the selection of L-368,899 as the development candidate on the basis of pharmacokinetic and metabolism observations. The presence of active N-demethylated metabolites of two other equipotent compounds in rats and dogs was found to be the major factor responsible for the discrepancy between oral bioavailability and efficacies observed for these 2 compounds. For L-368,899, a compound that demonstrated 20-40% oral bioavailability in rats, dogs, and chimpanzees, extensive first-pass metabolism rather than absorption was determined as the major factor responsible for the poor bioavailability (< 1%) in rhesus monkeys. In vitro metabolism studies with hepatic microsomes from rats, dogs, monkeys, and humans substantiated the conclusion that the rate of hepatic metabolism of L-368,899 in monkeys is faster than in the other species.

Animals↗
PubMedDate not supplied

The metabolism of DuP 753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey, and human liver slices.

The in vitro metabolism of DuP 753, a novel nonpeptide angiotensin II receptor antagonist, has been investigated in incubations with liver slice preparations from rats, monkeys and humans. Metabolites were identified by HPLC/MS, FAB/MS, Cl/MS, and/or 1H NMR. In the rat, the primary route of metabolism was oxidative, leading to either monohydroxylated or oxidized (carboxylic acid) metabolites, whereas in monkeys, glucuronidation of the tetrazole moiety predominated. An equal mixture of both oxidized and glucuronic acid-conjugated metabolites was isolated from incubations with human liver slices. All metabolites were tested in an in vitro assay to determine their activity as angiotensin II receptor antagonists. The monohydroxylated products and glucuronic acid conjugates were determined to be much less active than DuP 753. Biotransformation to the carboxylic acid, however, was shown to dramatically increase the activity of this agent. The in vivo duration of action of DuP 753 has been observed to be much longer in the rat than in the monkey. This may be explained, at least in part, by these in vitro metabolism studies. The predominance of glucuronidation observed in incubations with monkey liver slices would yield metabolites with diminished activity and might be expected to shorten the in vivo duration of DuP 753 in that species. The oxidative conversion to the carboxylic acid metabolite, along with the low level of glucuronidation observed in incubations with rat liver slices, may be responsible for the prolonged duration observed in vivo in the rat.

Animals↗
PubMedDate not supplied

Metabolic disposition of ivermectin in tissues of cattle, sheep, and rats.

The metabolic disposition of ivermectin, a new antiparasitic drug, has been studied in cattle, sheep, and also in rats dosed with the drug labeled with tritium in the C-22,23 positions. In the edible tissues of these animals, the unaltered drug was the major tissue residue component and was quantitated by HPLC-reverse isotope dilution assay. The depletion half-lives of the drug ranged between 1 and 6 days, similar to those of the total tissue residue in these species. Most metabolites present in the liver tissues were more polar than the parent drug. Based on spectral (NMR, mass spectrometric) analysis and chromatographic comparison with authentic compounds prepared by in vitro rat or steer microsomal incubations, three of these metabolites have been isolated and identified as the hydroxylation derivatives of ivermectin, i.e. 24-hydroxymethyl-H2B1a, its monosaccharide, and 24-hydroxymethyl-H2B1b.

Adipose Tissue↗
PubMedDate not supplied

Comparative metabolic disposition of ivermectin in fat tissues of cattle, sheep, and rats.

In the study of the metabolic disposition of ivermectin in cattle, sheep, and rats, a group of nonpolar metabolites was detected in the fat tissues of these animals. Upon saponification or esterase treatment, these nonpolar metabolites gave rise to polar products that were similar to the ivermectin metabolites present in the liver. A hypothesis was thus proposed that the polar ivermectin metabolites produced in the liver were esterified and stored in the fat as nonpolar entities, which can be reconverted back to the polar metabolites chemically or enzymatically. To substantiate this hypothesis, the regeneration of polar metabolites from the nonpolar metabolites was studied and hydrolysis products were characterized to establish the basic structure of the alcohol portion of the metabolites. Furthermore, chromatographic comparisons were made between radiolabeled in vivo metabolites and synthetic fatty acid ester samples. These results established the general structural class of the ivermectin nonpolar metabolites and also confirmed the unusual metabolic pathway of ivermectin disposition in fat tissue.

Adipose Tissue↗
PubMedDate not supplied

Metabolism of kadsurenone and 9,10-dihydrokadsurenone in rhesus monkeys and rat liver microsomes.

The metabolism of the PAF antagonists kadsurenone and tritium-labeled 9,10-dihydrokadsurenone was studied in rhesus monkeys and rat liver microsomes. The monkey metabolites of the two drugs were isolated as their glucuronide conjugates from the urine of iv dosed males. The metabolites from both monkey and microsomal metabolism were purified by reverse phase HPLC and identified by spectral (NMR, UV, and mass spectrometric) analysis. The principal pathway of biotransformation of the tritium-labeled 9,10-dihydrokadsurenone in monkeys was hydroxylation of the C-5 propyl side chain to give two metabolites, 10-hydroxy-9,10-dihydrokadsurenone and 9-hydroxy-9,10-dihydrokadsurenone. These compounds were excreted as glucuronides. Microsomal incubation of tritium-labeled 9,10-dihydrokadsurenone yielded the 10-, 9-, and 8-hydroxy-9,10-dihydrokadsurenone as major metabolites. Kadsurenone was also metabolized at the C-5 side chain, an allyl group. The monoglucuronide of 9,10-dihydroxykadsurenone was isolated from monkey urine. Spectral analysis was not definitive as to the site of conjugation, and the structure of the metabolite was assigned as the C-10 conjugate. A major metabolite of rat liver microsomal incubation of kadsurenone was 9,10-dihydroxykadsurenone.

Animals↗
PubMedDate not supplied

The metabolism of avermectin-H2B1a and -H2B1b by pig liver microsomes.

The avermectins are a new class of macrocyclic lactone disaccharide antiparasitic agents derived from Streptomyces avermitilis. On incubation of avermectin-H2B1a and avermectin-H2B1b with pig liver microsomes, a group of metabolites slightly more polar than the parent compounds were generated. Two major metabolites have been isolated and purified by repetitive reversed phase and normal phase HPLC. Their structures were established to be the O-demethylation products of the parent compounds, i.e. 3''-O-desmethyl-H2B1a and 3''-O-desmethyl-H2B1b. The structure assignments were based on spectral results of UV, NMR, fast atom bombardment-mass spectrometry, and chemical derivatization studies including acid hydrolysis as well as fluorogenic reaction. Among the in vitro metabolites, there was only a trace amount of the polar metabolites 24-hydroxymethyl-H2B1a and 24-hydroxymethyl-H2B1b which were the major in vitro metabolites of avermectin-H2B1a and -H2B1b by steer or rat liver microsomes.

Animals↗
PubMedDate not supplied

N-glucuronidation reactions. I. Tetrazole N-glucuronidation of selected angiotensin II receptor antagonists in hepatic microsomes from rats, dogs, monkeys, and humans.

In vitro conditions for the preparation of tetrazole N2-glucuronides using liver microsomes (enriched with UDP-glucuronic acid) from rats, dogs, monkeys, and humans have been developed and optimized. The structures of tetrazole N2-glucuronides of 3 biphenyl tetrazole-containing angiotensin II (AII) receptor antagonists MK-954 (I), L-158,338 (II), and L-158,809 (III), and a model compound methyl biphenyl tetrazole (IV) were determined either by NMR and mass spectrometry or by comparison of HPLC retention times with that from authentic compounds. The species difference as well as gender difference in the rate of the in vitro reaction were compared. The optimal pH for the reaction was determined to be 5.0 with liver microsomes from monkeys and humans, and 6.2 with those from rats and dogs. For the model compound IV, the rate of N2-glucuronidation by liver microsomes from rats, dogs, and monkeys was approximately 10-fold faster than that by humans. For the AII receptor antagonists I, II, and III, the rate of the same reaction by liver microsomes from dogs and monkeys was much faster than that by humans. The relative intrinsic rate of this reaction for these three substrates ranked similarly in rats and humans as II > III > I. With compound I, a biphenyl tetrazole-containing imidazole derivative that has potential sites for both O- (primary hydroxyl) and N2-(tetrazole) glucuronidation, both O- and tetrazole N2-glucuronides were formed by liver microsomes from rats and monkeys (at neutral pH), whereas N2-glucuronide was the only product from dogs and humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMedDate not supplied

N-glucuronidation reactions. II. Relative N-glucuronidation reactivity of methylbiphenyl tetrazole, methylbiphenyl triazole, and methylbiphenyl imidazole in rat, monkey, and human hepatic microsomes.

The relative intrinsic in vitro N-glucuronidation reactivity of three classes of heterocyclic compounds was compared using model compounds incubated with UDP-glucuronic acid-enriched liver microsomes from rats, monkeys, and humans. These compounds, all methylbiphenyl (MB) derivatives, represent three classes of N-containing heterocycles commonly used in the design of new drug entities [i.e MB-tetrazole, MB-triazole, (1,2,3- and 1,2,4-), and MB-imidazole (C2- and C4-substituted)]. The structures of all respective N-glucuronides generated from microsomal incubations were determined by Nuclear Overhauser Effect difference NMR spectroscopy. The chemical and enzymic stabilities of N-glucuronides were also studied. In general, relatively low reactivity was found at nitrogens located next to substituted carbons in heterocycles such as N3 in MB-C4-imidazole, N3 in MB-1,2,3-triazole, N2 (or N4) in MB-1,2,4-triazole, and N1 (or N4) in MB-tetrazole. MB-C2-imidazole, in which both nitrogens are in immediate neighboring positions of the substituted carbon, was unreactive toward N-glucuronidation. When the rate of N-glucuronidation was compared under optimal reaction conditions for each compound, most compounds showed higher reactivity with liver microsomes from monkeys than those from rats, except for N2-glucuronidation of MB-tetrazole and MB-1,2,3-triazole. However, the trend for the relative N-glucuronidation reactivity of these compounds by liver microsomes from humans is quite different from those by monkeys and rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗