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H M Siefert

Publications and source records attributed to H M Siefert.

At least 19 recordsLinked to original sources
PubMed1999

Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: tissue distribution in male rats.

BAY 12-8039 (moxifloxacin-HCl) and 14C-labelled BAY 12-8039 were administered to male rats as single i.v. and oral doses of 4.6 and 5.0 mg/kg bodyweight respectively. The distribution of substance-associated radioactivity in the body was investigated by whole-body autoradiography. The concentrations of the unchanged compound in plasma, skin suction blister fluid and lung tissue were determined by HPLC. Whole-body autoradiography revealed distinctly higher concentrations of radioactivity in the gastrointestinal tract, urinary bladder and in most organs and tissues (e.g. kidneys, liver, spleen, lungs, various glands, cartilaginous tissues and in melanin-containing structures located in the eye, meninges and hair follicles of pigmented skin) than in blood. Radioactivity crossed the blood-brain barrier only to a small extent. The results show a high tissue affinity and a rapid and homogeneous distribution of radioactivity from blood to organs or tissues. No relevant difference in the distribution of radioactivity was found following i.v. and oral administration. After i.v. and oral dosing similar concentrations of the unchanged compound were determined in skin suction blister fluid and plasma. The concentrations of the unchanged compound in lung tissue were about three times higher than those in plasma following both i.v. and oral administration. The concentration-time courses for moxifloxacin in plasma and lung tissue were parallel.

Animals↗
PubMed1999

Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species.

The pharmacokinetics of moxifloxacin was investigated in NMRI mice, Wistar rats, rhesus monkeys, beagle dogs, Göttingen minipigs and healthy human volunteers after i.v. and oral administration of moxifloxacin-HCl (single doses of moxifloxacin 9.2 mg/kg bodyweight) in animals and 100 mg moxifloxacin (1.4 mg/kg bodyweight p.o. and 1.2 mg/kg bodyweight i.v.) in humans. The plasma concentration vs time courses of the unchanged compound (determined by HPLC) and the derived pharmacokinetic parameters were used to evaluate the absorption process, to compare the pharmacokinetics in these species and to perform an interspecies scaling. The results of the pharmacokinetic investigations indicate a clear dependence on the species. Moxifloxacin is absorbed quickly (rats, dogs, humans > monkeys): the major portion of the dose reached the systemic circulation within the first 2 h. In the minipig absorption was slower. Bioavailability was high to moderate (91-52%) in all species. Protein binding (f(u)) was low (55-71%) in all species. The volume of distribution at steady state (Vss) was medium to large (2.0-4.9 L/kg) in all species. There were considerable differences in maximum concentrations (C(max,norm), 0.430-0.070 kg/L) and in AUCnorm values (oral, 6.18-0.184 kg x h/L; i.v., 7.51-0.237 kg x h/L). Total body clearance (CL) decreased with increasing bodyweight (4.21-0.132 L/(h x kg)). The mean residence time (MRT) decreased with decreasing bodyweight (15-0.88 h). The half-life (t(1/2)) decreased with decreasing bodyweight (oral, 12-1.3 h, i.v., 13-0.93 h). There was moderate to low renal excretion (i.v., 20-6.2%), the renal clearance, (CL(R)) was in the range 0.615-0.0222 L/(h x kg). Regarding the pharmacokinetic parameters determined after oral administration, the dog was most similar to the human in terms of Cmax, AUC and t(1/2). There was good correlation between bodyweight and CL (coefficient of correlation (r) = 0.959), Vss (r = 0.990) and MRT (r = 0.943). On the basis of preclinical studies a terminal half-life appropriate for once-daily dosing in humans was predicted and confirmed by Phase I data.

Animals↗
PubMed1997

Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 1st communication: absorption, concentrations in plasma, metabolism, and excretion after single administration to rats and dogs.

The absorption, concentrations in plasma, metabolism and excretion of ramatroban ((+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been studied following a single intravenous, oral, or intraduodenal administration of 14C-labeled or nonlabeled compound to rats and dogs (dose range: 1-10 mg.kg-1). After intraduodenal administration of [14C]ramatroban, enteral absorption of radioactivity was rapid and almost complete both in bile duct-cannulated male rats (83%) and female dogs (95%). The oral bioavailability of ramatroban was complete in the dog but amounted to about 50% in the rat due to presystemic elimination. A marked food effect on the rate but not on the extent of absorption was observed in rats. The elimination of the parent compound from plasma occurred rapidly with total clearance of 1.2 l.h-1.kg-1 in male rats and 0.7 l.h-1.kg-1 in dogs. After oral administration to male rats AUC increased dose-proportionally between 1 and 10 mg.kg-1, whereas in Cmax an over-proportional increase was observed. Excretion of total radioactivity was fast and occurred predominantly via the biliary/fecal route in both species. The residues were low, 144 h after dosing less than 0.2% of the radioactivity remained in the body of rats. A considerable sex difference was found in rats following oral administration of ramatroban. In females a 3-fold higher AUC and a 1.7-fold longer half-life of unchanged compound, as well as 3-fold higher renal excretion of total radioactivity was observed. A marked species difference exists in the metabolism of ramatroban. In dogs the drug was almost exclusively metabolized via conjugation with glucuronic acid, whereas in rats oxidative phase I metabolism and glucuronidation were equally important. As a consequence enterohepatic circulation was much more pronounced in dogs (77%) than in rats (17% of the initial dose).

Administration, Oral↗
PubMed1992

Biotransformation of nifedipine in rat and dog.

Following oral and/or intraduodenal administration, the biotransformation of 14C-labelled nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylate, Bay a 1040, Adalat, CAS 21829-25-4) has been reinvestigated in rats and dogs (dose: 5 mg/kg body weight in both species) to complete the metabolic data. Thirteen metabolites were isolated from the perfusate and bile of the isolated perfused rat liver model. Their structures were elucidated by spectroscopic methods (FAB-MS, combined GC/MS, NMR). The analyzed samples were used for the chromatographic (HPLC) comparison with urine and bile from the in vivo studies. The metabolites identified in rat urine (oral dose) account for 47.4% of the dose administered. 82.8% (rat) and 62.8% (dog) of the dose, resp., could be attributed to known structures in urine and bile following intraduodenal administration. Based on the structures identified the following biotransformation steps occurred: dehydrogenation of the 1,4-dihydropyridine system, hydroxylation of the methyl groups at 2- or 6-position followed by glucuronidation or by subsequent oxidation to the carboxylic acid, and oxidative ester cleavage.

Administration, Oral↗
PubMed1991

Biotransformation of nitrendipine in rat, dog, and mouse.

14C-Labelled Nitrendipine (Bay e 5009; Baypress, Bayotensin; CAS 39562-70-4) was administered by the oral and intraduodenal route to rats, dogs, and mice (oral dosing only) to elucidate the biotransformation pathways in these three species. The drug was extensively metabolized: 20 biotransformation products were identified by comparison with synthetic reference compounds using two-dimensional TLC, HPLC, GC/radio-GC, combined GC/MS (EI-, CI-mode), FAB-MS, and 1H-NMR-spectroscopy. The metabolites identified accounted for approx. 72 to 73% of the dose administered in rats and dogs (bile and urine) and 48 to 56% in male and female mice (urine only). Based on the structures identified the following biotransformation reactions occurred: Dehydrogenation of the 1,4-dihydropyridine (primary metabolic step), oxidative ester cleavage as further basic biotransformation reaction (also at the dihydropyridine state), hydroxylation of the methyl groups in 2- or 6-position as separated and important metabolic reaction (at the dihydropyridine as well as pyridine state), reduction of the aromatic nitro group (important only in mice) and subsequent acetylation (dog only), and glucuronidation as phase II reaction forming ether and ester type glucuronides.

Animals↗
PubMed1989

Pharmacokinetics of rioprostil in rats.

The pharmacokinetics of rioprostil in rats has been investigated following a single intravenous or oral dose of rioprostil between 0.004 and 10 mg/kg. Rioprostil is eliminated from plasma following an intravenous dose rapidly (t1/2 = 0.22 h) and nearly exclusively by biotransformation. The high total clearance (CL = 5.4 l.h-1.kg-1) indicates an additional extrahepatic metabolism. A systemic bioavailability of 2%, in spite of a rapid and nearly complete absorption (fa = 90%), indicates an extended first-pass effect. Twenty-four hours after the administration of [3H]rioprostil the residual radioactivity in the animal amounted to less than 1% of the dose administered.

Animals↗
PubMed1989

Pharmacokinetics of acarbose. Part II: Distribution to and elimination from tissues and organs following single or repeated administration of [14C]acarbose to rats and dogs.

Acarbose (O-4,6-dideoxy-4-[[1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)-2-cyclohexen-1-yl]amino]-alpha-D-glucopyranosyl- (1----4)-O-alpha-D-glucopyranosyl-(1----4)-D-glucopyranose, Bay g 5421) labelled with 14C was administered to male rats, pregnant and lactating rats as well as to female dogs with single intravenous or oral doses (2 or 4 mg.kg-1) and with repeated oral doses of 2 mg.kg-1 to male rats for 3 weeks. The distribution of radioactivity to organs and tissues, the placental transfer and the secretion into milk was studied using whole-body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy. Unchanged [14C]acarbose was distributed predominantly in the extracellular space, as observed after intravenous dosing to rats. According to the main excretion route, high concentrations were found in kidneys and urine and additionally in blood, lung, and connective tissue or interstitial space. The permeability of the blood/brain barrier for [14C]acarbose and/or its metabolites was very low. No indication was found for distinct differences in the distribution patterns in rats and dogs after intravenous and also in dogs after oral administration. In contrast, in rats after oral dosing the distribution pattern of radioactivity was different with relatively high concentrations in liver, kidney, adrenal gland, spleen, and intestinal mucosa. Due to the slow absorption of the microbial degradation products of [14C]acarbose from the intestine maximum concentrations in the different tissues were reached 8-24 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Acarbose↗
PubMed1988

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine.

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1988

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs.

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).

Absorption↗
PubMed1988

The pharmacokinetics of nitrendipine. II. Distribution to and elimination from organs and tissues of rats and dogs after single or repeated administration of [14C]nitrendipine.

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to male rats, pregnant and lactating female rats, and female dogs intravenously or orally once as well as to male rats repeatedly over a period of 4 weeks (rat 5 (and 10) mg/kg, dog approximately 3 mg/kg). The distribution of radioactivity (unchanged compound and metabolites) was investigated using whole-body autoradiography as well as quantitative measurements of the organ and tissue concentrations of radioactivity after necropsy. [14C]nitrendipine was distributed rapidly and heterogeneously into the organs and tissues of rats. Already 24 h after administration most of the radioactivity had reached the gastro-intestinal (GI) tract via biliary secretion. High concentrations were also detectable in liver and kidneys. The radioactivity was eliminated from the tissues with terminal half-lives lying between 52 (plasma) and 360 h (muscle). Only 0.13% of the administered radioactivity was detectable in the body (excl. GI-tract) after 10 days. In dogs, the distribution pattern was similar to that observed in rats. After 28 daily administrations of [14C]nitrendipine to male rats the plasma and tissue equivalent concentrations were 3 (plasma) to 12 times (adipose tissue) higher than after single administration. The half-lives were increased by 20 to 70%, lying between 2 and 15 days. There were no indications for any specific retention of the radioactivity. The radioactivity from [14C]nitrendipine was secreted into the milk of lactating rats and crossed the placental barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1986

Pharmacokinetics of ciprofloxacin. 2nd communication: distribution to and elimination from tissues and organs following single or repeated administration of [14C]ciprofloxacin in albino rats.

1-Cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3-quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) was administered to male and to pregnant albino rats with single intravenous or oral doses of 5 or 10 mg/kg body weight and with repeated oral doses of 5 mg/kg (7 consecutive daily administrations to male rats). Following a single intravenous administration the [14C]ciprofloxacin related radioactivity was distributed rapidly and differentiated to the body. Compared to plasma high concentrations were determined in kidney, liver, skeleton muscle, pancreas, testes and cartilage, low concentrations occurred in brain and adipose tissue. In some selected tissues radioactivity was largely due to unchanged [14C]ciprofloxacin (57% to 100%). A good penetration of total radioactivity into tissues and organs with a similar distribution pattern as detected after intravenous dosing also occurred after a single oral administration. Highest concentrations were determined 1 h after dosing. Compared to plasma most tissues and organs showed higher concentrations and higher AUC-values. For brain and eye low values were determined. Compared to plasma a longer mean residence time of radioactivity was calculated for brain, eye, eye-wall, testes and blood cells. 6 d after single administration the radioactive residues in the body exclusive gastrointestinal tract amounted to less than 0.1% of the dose. Following a seven-day treatment the distribution pattern of total radioactivity in the body did not differ essentially from that after single dosing. Compared to single dosing AUC-values higher by the factor 2 to 4 were calculated after repeated administration for plasma and most of the tissues and organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys.

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey.

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.

Animals↗
PubMed1983

Pharmacokinetic studies following systemic and topical administration of [14C]bifonazole in man.

[14C]Bifonazole (1-[(4-Biphenylyl)-phenylmethyl]-1H-imidazole, Bay h 4502, Mycospor) was administered systemically (i.v.) and topically (dermally) in different formulations to a total of 17 volunteers. In the serum, the concentrations of total radioactivity and of the unchanged drug were determined by liquid scintillation counting techniques and by thin-layer densitometry, respectively. Urine and feces were collected and radioassayed. The extent of percutaneous absorption was calculated. In addition, distribution of the unchanged drug in the layers of the skin was studied radiometrically in three patients. After intravenous administration, bifonazole was eliminated from the serum largely in metabolized form. The half-lives of elimination of the radioactivity from the serum were approximately 7 and 42 h. Within 5 days 45% of the dose was excreted with the urine, and 39% with the feces. After topical application to healthy skin areas, under occlusive conditions, less than 1% of bifonazole was absorbed percutaneously from a 1% solution or cream, and the amount absorbed was excreted with the urine and the feces in approximately the same proportions as after i.v. administration. Following administration of the drug to inflamed skin, the proportion absorbed was 3 to 4% of the dose administered and thus higher than after application to normal skin. Studies on depth localization showed that the drug has a high capacity for skin penetration. Even in the lower layers of the epidermis, bifonazole was present in amounts several times as high as the minimum inhibitory concentrations for dermatophytes measured in vitro.

Administration, Topical↗
PubMed1982

[Indirect lymphography at the eye and in the face- and neck-region with iotasul (author's transl)].

For the first time the lymphatic pathways of the conjunctiva and the eyelids of dogs could be presented in vivo with the water-soluble X-ray contrast medium iotasul. By means of indirect application the lymph flow could be demonstrated up to the truncus jugularis. Because of the simultaneous infusion of the contrast medium at different points the lymphography of the face- and neck-region is considerably facilitated.

Animals↗