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Biomedical subjects

E H Ulm

Publications and source records attributed to E H Ulm.

At least 19 recordsLinked to original sources
PubMed2001

Bexarotene metabolism in rat, dog, and human, synthesis of oxidative metabolites, and in vitro activity at retinoid receptors.

The metabolism of bexarotene, a rexinoid recently approved in the United States for treatment of cutaneous T-cell lymphoma, was studied using liver slices from untreated rats and dogs, liver microsomes from untreated and pretreated rats, and pooled human liver microsomes. Metabolite profiles were examined in bile and plasma from rats and dogs, and plasma from humans treated with bexarotene. Four metabolites, racemic 6-hydroxy-bexarotene, racemic 7-hydroxy-bexarotene, 6-oxo-bexarotene, and 7-oxo-bexarotene, were synthesized and their binding to, and transactivation of retinoid receptors were examined. Qualitatively similar metabolite profiles were observed in the microsomal and liver slice extracts; the predominant metabolites were 6-hydroxy-bexarotene and glucuronides of parent or hydroxylated metabolites. Pretreatment of rats with bexarotene induced hepatic microsomal bexarotene metabolism. The hydroxy and oxo metabolites were observed in plasma of rats, dogs, and humans treated with bexarotene and 6-hydroxy-bexarotene was a major circulating metabolite. The oxidative metabolites were more abundant relative to parent in plasma from humans than from rat or dog. The predominant biliary metabolites in rat and dog were bexarotene acyl glucuronide and a glucuronide of oxidized bexarotene, respectively. Since bexarotene elimination is primarily biliary in these species, these metabolites represent the main bexarotene metabolites in rats and dogs. The binding of synthetic metabolites to retinoid receptors was much reduced relative to parent compound. The metabolites exhibited minimal activity in transactivating retinoic acid receptors and had reduced activity at retinoid X receptors relative to bexarotene. Thus, while there is substantial systemic exposure to the oxidative metabolites of bexarotene, they are unlikely to elicit significant retinoid receptor activation following bexarotene administration.

Animals↗
PubMed1999

A Phase I study of LGD1069 in adults with advanced cancer.

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.

Adult↗
PubMed1998

Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid x receptor selectivity and effects on metabolic enzymes.

Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two families of retinoid receptors, i.e. retinoic acid receptors (RAR) and retinoid X receptors (RXR), for which the various synthetic and naturally occurring retinoids have differing selectivities. The synthetic analogs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1550 is highly RAR-selective. Naturally occurring all-trans-retinoic acid (Tretinoin) has a degree of selectivity for RAR, whereas ALRT1057 (9-cis-retinoic acid, Panretin) is equally active at RAR and RXR (i. e. a pan-agonist). To evaluate the effects of these compounds on metabolic enzymes, male Sprague-Dawley rats received daily oral doses for 4 days, and liver microsomes were prepared on day 5. As a class, these ligands exerted profound effects on hepatic microsomal metabolic enzyme levels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatment, whereas those exerting predominantly RXR activity increased these parameters. A similar relationship was observed when glucuronidation was examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selective for RXR. However, both RAR- and RXR-selective ligands decreased CYP1A2, whereas they induced CYP4A. Although the mechanisms underlying these effects are not known, these results suggest that RAR- and RXR-binding ligands exert distinct effects on hepatic metabolism, and they indicate the potential for drug-drug interactions, especially involving CYP3A. The nature of such interactions would depend on the RAR/RXR selectivity of the ligand and the P450 isozymes responsible for the metabolism of coadministered drugs.

Animals↗
PubMed1998

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Administration, Oral↗
PubMed1996

Oxidative and reductive metabolism of 9-cis-retinoic acid in the rat. Identification of 13,14-dihydro-9-cis-retinoic acid and its taurine conjugate.

9-cis-Retinoic acid (9-cis-RA), a hormone that binds and activates all known retinoid receptor subtypes, is structurally similar to all-trans-retinoic acid and may share common metabolic fates. Both oral and intravenous doses of 9-cis-RA to rats led to hydroxylation and ketone formation at carbon-4. 9-Cis-RA also isomerized in vivo to 13-cis-retinoic acid, 9-cis, 13-cis-retinoic acid, and all-trans-retinoic acid. After administration of [11-3H]9-cis-RA, the proportion of plasma radioactivity that was volatile increased over time, which suggested that beta-oxidative chain-shortening of 9-cis-RA might occur. An equimolar mixture of [1-13C2H3]9-cis-RA and 9-cis-RA was administered to rats for stable-isotope-labeled metabolite production. A chromatographic peak that had a lambdamax = 290 nm vs. 348 nm for the parent compound, had a retention time similar to the parent, and yielded a 1:1 positive-ion isotope cluster at m/z 303/307 in its mass spectrum. NMR analysis revealed 9-cis and 13,14-dihydro configurations, indicating that 9-cis-RA can be metabolized in rat by reduction to 13,14-dihydro-9-cis-RA. An earlier-eluting HPLC peak that exhibited a lambdamax at 290 nm, and a negative-ion-MS isotope cluster at m/z 408/412 was observed during separations of rat liver extracts. LC/MS/MS analysis revealed product ions for this peak diagnostic for carboxylic acid taurine conjugates. In rats, reduction of 9-cis-RA to 13,14-dihydro-9-cis-RA may represent an initial step leading to beta-oxidation, although available data demonstrate it is conjugated with taurine to form a novel metabolite.

Animals↗
PubMed1996

Initial clinical trial of the retinoid receptor pan agonist 9-cis retinoic acid.

The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 4 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels. 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. No major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration.

Adult↗
PubMed1995

Pharmacokinetics of 9-cis-retinoic acid in the rhesus monkey.

9-cis-Retinoic acid is a naturally occurring biologically active retinoid capable of binding and transactivating both the retinoic acid receptors and the retinoid X receptors. A study was performed to characterize the pharmacokinetics 9-cis-retinoic acid following i.v. bolus administration in the nonhuman primate. Groups of three animals received i.v. bolus doses of 9-cis-retinoic acid of either 50 or 100 mg/m2. Blood and cerebrospinal fluid samples for determination of 9-cis-retinoic acid concentration were obtained prior to and 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 min following drug administration. The plasma drug concentration profile of 9-cis-retinoic acid was consistent with a first-order elimination process, with a harmonic mean half-life of 31 min, and a mean clearance of 97 ml/min/m2. The pharmacokinetics of 9-cis-retinoic acid were linear over the dose range studied. Plasma concentrations of all-trans-retinoic acid following 9-cis-retinoic acid administration were less than the limit of quantitation (0.1 microM), suggesting that isomerization to all-trans-retinoic acid is not a major metabolic pathway. In contrast to all-trans-retinoic acid, the elimination of 9-cis-retinoic acid did not appear to be capacity limited (saturable). Previous studies in the Rhesus monkey have shown that repeated dosing with all-trans-retinoic acid leads to a reduction of this saturable component of elimination and results in reduced exposure to drug. These studies, in an animal model highly predictive of humans, suggest that declines in plasma concentrations of 9-cis-retinoic acid as a result of its repeat administration at doses up to 100 mg/m2 will not occur.

Animals↗
PubMed1988

Renin inhibitors containing hydrophilic groups. Tetrapeptides with enhanced aqueous solubility and nanomolar potency.

Nineteen tetrapeptides containing statine (Sta) and 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) were prepared. Solubility measurements of these compounds were carried out in H2O and in pH 7.4 phosphate buffer solution, and their partition coefficients were determined in a 1:1 1-octanol/sodium phosphate-citric acid buffer system. The tetrapeptides were tested in vitro for their ability to inhibit porcine, canine, and human plasma renins. Four compounds, 6, 12, 14, and 20, were potent inhibitors against all renins tested (IC50 = 10(-9) M). Compound 12 was administered orally to dogs and substantially inhibited plasma renin activity for up to 5 h. The addition of polar groups to the C-terminus of Sta- and ACHPA-containing tetrapeptides renders them soluble in aqueous milieu and provides a valuable tool with which to examine the role of the renin-angiotensin system in physiological and pathological circumstances.

Amino Acids↗
PubMed1987

Renin inhibitors. Statine-containing tetrapeptides with varied hydrophobic carboxy termini.

A series of statine-containing tetrapeptides, systematically modified at the carboxy terminus with various hydrophobic aromatic groups, is described. These compounds were tested in vitro for their ability to inhibit porcine, human plasma, and purified human kidney renins. These analogues help to define optimal binding aspects in a region of the enzyme that appears to be specific for spatial arrangement of aromatic groups. Replacement of the metabolically labile Phe amide with nonpeptidal groups proved possible while achieving inhibitory potency in the nanomolar range vs. porcine kidney renin. For the compounds 6i, 6m, and 6o, a large discrepancy in potency between the human plasma and the purified human kidney renin assays was observed. This disparity does not appear to be a consequence of a previously proposed plasma binding component.

Amino Acids↗
PubMed1987

Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats.

The relative contribution of ether and ester glucuronidation to diflunisal metabolism was assessed by studying the effects of enzyme inducers, phenobarbital (PB), 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF). Treatment with either PB, 3-MC or BNF increased markedly the unbound intrinsic clearance of diflunisal. Saline-treated control rats showed a greater unbound intrinsic clearance of diflunisal than oil-treated controls indicating that repetitive treatment with oil had an effect on enzyme activity. Treatment with 3-MC and BNF appeared to cause a decrease in the biliary clearance of ether and ester glucuronide, but PB had little effect on the biliary clearance of glucuronides. Rats pretreated with PB showed a 3-fold increase in the fractional metabolite formation clearance of ether glucuronide and a 2-fold increase in the fractional metabolite formation clearance of ester glucuronide, suggesting differential effects of PB on ester and ether glucuronidation. A similar trend, but to a smaller extent, was also observed for 3-MC- and BNF-treated rats. These results suggest the possibility of selective induction of multiple forms of UDP-glucuronyltransferase involved in metabolism of diflunisal.

Animals↗
PubMed1986

Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.

A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Possible mechanisms for reduced plasma clearance of diflunisal in rat experimental renal failure.

To provide insight into the reported reduction in the plasma clearance of diflunisal in human renal failure, this investigation evaluated several possible mechanisms for this effect in experimental renal failure. Rats with renal failure, induced by uranyl nitrate or by ureteral ligation, had both a lower plasma clearance and an increased apparent volume of distribution, a pattern resembling that seen in human renal failure. Steady-state diflunisal concentration and unbound fraction were determined in studies during a constant infusion of diflunisal to establish the relationships of concentration, protein binding and intrinsic clearance. The infusion studies revealed that the intrinsic clearance of diflunisal, i.e., the ability of enzyme system(s) to metabolize the drug, was decreased in uremia. Also, plasma protein binding of diflunisal was decreased, which may explain the increase in apparent volume of distribution in uremic rats. The decreased intrinsic clearance of diflunisal in uremic rats may be due partly to saturation of biotransformation process(es) by increasing unbound concentration as a consequence of impairment of plasma protein binding of diflunisal, and partly due to the diminished enzyme activity of glucuronidation by renal failure. The lack of an effect of the esterase inhibitor phenylmethylsulfonyl fluoride on the intrinsic clearance of diflunisal in uremic rats suggested that the reduced intrinsic clearance of diflunisal was not attributable to the systemic enzymatic hydrolysis of the ester glucuronide.

Animals↗
PubMed1985

Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine.

Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin. Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA-L -leucyl-L- phenylalanyl amide [Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3], with renin inhibitions of Ki = 1.6 X 10(-10) M (human kidney renin), IC50 = 1.7 X 10(-10)M (human plasma renin), IC50 = 1.9 X 10(-9)M (dog plasma renin), and IC50 = 2.1 X 10(-8) M (rat plasma renin). This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1. Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies. Structure-activity results are presented that show the minimal N-terminus for these inhibitors. An ACHPA-containing pentapeptide, N-[(ethyloxy)carbonyl]-L-phenylalanyl-L- histidyl-ACHPA-L-leucyl-L-phenylalanyl amide [Etoc-Phe-His-ACHPA-Leu-Phe-NH2,8], retained subnanomolar inhibitory potency. Molecular modelling studies are described that suggested the design of ACHPA.

Amino Acids↗
PubMed1985

Angiotensin-converting enzyme inhibitors: synthesis and biological activity of acyl tripeptide analogues of enalapril.

The synthesis and biological activity of a series of inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) are described. Incorporation of the substituted N-carboxymethyl dipeptide design of enalapril (MK-421) into acyl tripeptides and larger peptides yielded potent inhibitors of the enzyme. These can be viewed as substrate analogues in which the carbonyl of the scissile peptide bond is replaced by a CHCO2H group. Several of the analogues described possess inhibitory potency equal to that of enalaprilat (MK-422), but none achieves an increase in potency which would demonstrate additional binding interactions contributed by the extended peptide chain. Application of the design described may be useful for inhibition of other metallopeptidases.

Angiotensin-Converting Enzyme Inhibitors↗