RESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. RESULTS: The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Proteínas de Transporte de Monossacarídeos/metabolismo , Neoplasias/metabolismo , Mostardas de Fosforamida/efeitos adversos , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Glucose/análogos & derivados , Humanos , Ifosfamida/análogos & derivados , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Monossacarídeos/biossíntese , Neoplasias/tratamento farmacológico , Mostardas de Fosforamida/administração & dosagem , Mostardas de Fosforamida/farmacocinéticaRESUMO
PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/farmacologia , Modelos Biológicos , Pré-Menopausa/sangue , Adulto , Compartimentos de Líquidos Corporais , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/antagonistas & inibidores , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/farmacocinética , Antagonistas de Hormônios/sangue , Antagonistas de Hormônios/farmacocinética , Humanos , Injeções Subcutâneas , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/sangue , Computação Matemática , Pré-Menopausa/efeitos dos fármacos , Progesterona/antagonistas & inibidores , Progesterona/sangue , Método Simples-CegoRESUMO
In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.
Assuntos
Anfetaminas/farmacologia , Teofilina/análogos & derivados , Anfetaminas/metabolismo , Animais , Depressores do Apetite , Interações Medicamentosas , Etanol/farmacologia , Hexobarbital/farmacologia , Humanos , Técnicas In Vitro , Fígado/metabolismo , Mazindol/farmacologia , Atividade Motora/efeitos dos fármacos , Ratos , Teofilina/metabolismo , Teofilina/farmacologiaRESUMO
The monoamine oxidase (MAO) B activity of rat brain was inhibited by selegiline and its desmethyl-metabolite in vitro with IC50-values of 11.25 nmol/l and 625.00 nmol/l, respectively. When measured in an ex vivo experiment following oral treatment of rats, the large difference in potency was distinctly reduced, from factor 60 in vitro to factor 3 ex vivo. Restoration experiments of MAO-B-activity after cessation of treatment revealed a nearly identical time course for both compounds. It is concluded that desmethyl-selegiline is an irreversible blocker of MAO-B, nearly equipotent to selegiline after multiple oral administration. No pharmacologically relevant inhibition of MAO-A was found with both compounds.
Assuntos
Anfetaminas/farmacologia , Monoaminoxidase/metabolismo , Selegilina/farmacologia , Administração Oral , Animais , Clorgilina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Cinética , Masculino , Pargilina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The objective of this study was to determine the impact of prolonged gastric emptying in patients with insulin dependent diabetes mellitus (IDDM) on the bioavailability of the R(+)- and S(-)-thioctic acid (TA) enantiomers. Gastric emptying time (GET) was assessed in 30 healthy volunteers and 22 patients with IDDM using sequential ultrasonography after a standardized solid-liquid test meal. Pharmacokinetics and absolute bioavailability (F) of the TA-enantiomers were studied using a randomized, open two-way crossover design with administrations of oral and intravenous single doses of 200 mg rac-TA. GET in healthy subjects was 134.7+/-21.6 min, the normal range was calculated from 88.3 to 181.1 min. The mean GET in all IDDM patients was significantly prolonged (178.2+/-28.1 min; P<0.001). Only 50% of the patients (n=11) were found to have normal GET (group A), the other half of the population (n=11) were considered to have delayed GET (group B). Mean GET values were 156.9+/-21.5 in group A (P=0.028) and 199.4+/-13.9 min in group B, respectively, suggesting that gastric motility is significantly different from non-diabetic controls even in patients with apparently normal gastric emptying. Times to peak plasma concentrations (t(max)) of both TA-enantiomers were similar in both groups and thus, unrelated to measures of gastric emptying. In contrast, maximum concentrations (C(max)) and area-under-the-curve values (AUC) of both enantiomers were reduced by about 30% in patients with delayed GET. Although these differences resulted in statistical significance for the AUC of both enantiomers (P<0.05), linear regression analysis showed only modest correlation between GET and the extent of TA-enantiomer absorption (r2=0.31 and 0.22 for R(+)-/S(-)-TA, respectively). The study suggests that prolonged gastric emptying is frequently present in IDDM. Delayed gastric emptying, however, does not substantially affect the rate and extent of absorption of both TA-enantiomers.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Esvaziamento Gástrico/fisiologia , Ácido Tióctico/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estereoisomerismo , Ácido Tióctico/administração & dosagem , Ácido Tióctico/química , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/sangue , Complexo Vitamínico B/farmacocinéticaRESUMO
Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.
Assuntos
Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/farmacocinética , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacocinética , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/efeitos adversos , Meia-Vida , Humanos , Masculino , Análise de Regressão , Estereoisomerismo , Ácido Tióctico/efeitos adversosAssuntos
Benzenossulfonatos/farmacologia , Carcinoma de Ehrlich/metabolismo , Ácidos Ftálicos/farmacologia , Ácidos Sulfanílicos/farmacologia , Compostos de Sulfidrila/metabolismo , Reagentes de Sulfidrila/farmacologia , 4-Nitrofenilfosfatase/metabolismo , Animais , Feminino , Iodoacetatos/farmacologia , Cinética , Camundongos , Peso Molecular , Relação Estrutura-Atividade , Ácidos Sulfanílicos/análogos & derivadosRESUMO
Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups: (1) absence of GS (non-GS)/rapid acetylator (RA) (N=11); (2) GS/RA (N=8); (3) non-GS/SA (N=11); (4) GS/SA (N=7). Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple-dose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P=0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.
Assuntos
Anticonvulsivantes/farmacocinética , Arilamina N-Acetiltransferase/genética , Carbamatos/farmacocinética , Doença de Gilbert/genética , Fenilenodiaminas/farmacocinética , Polimorfismo Genético , Acetilação , Análise de Variância , Anticonvulsivantes/sangue , Carbamatos/sangue , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Fenilenodiaminas/sangueRESUMO
The pharmacokinetics of the analgesic flupirtine (ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamate, D 9998) were examined in healthy volunteers after a single intravenous, peroral and rectal dose. Plasma-and urine concentrations were analysed by a photometric procedure specific for flupirtine and its active metabolite D 13223. The bioavailability from the capsule amounted to 90%, from the suppository to 72.5%. Plasma half-life was 8.5-10.7 h. No significant accumulation of the plasma concentrations after multiple peroral administration was observed. After a peroral dose of 14C-flupirtine the radioactivity is predominantly excreted via the urine (72%). Two metabolites could be isolated from urine and their chemical structure determined. Together with the parent drug they explain 54% of the urinary radioactivity. The metabolite D 13223 that still has some analgesic activity is found in plasma, too. The portion of unchanged flupirtine amounts to 56-83% of the total plasma levels.
Assuntos
Aminopiridinas/metabolismo , Analgésicos/metabolismo , Adulto , Aminopiridinas/urina , Analgésicos/urina , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Feminino , Humanos , Cinética , Masculino , Espectrometria de Massas , FotometriaRESUMO
Pharmacokinetics and biotransformation of 14C-labelled ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carbama te maleate (flupirtine maleate, D 9998 maleate) was studied in rats and dogs. The drug was rapidly and completely absorbed after peroral administration in both species. The kinetics of the plasma levels after intravenous administration show a short distribution phase followed by an elimination phase with half-lives between 2 and 3 h. Similar half-lives were observed after peroral administration: 2.2. h in the rat and 2.6 h in the dog. Renal excretion amounts to 20% (rat) and 36% (dog) after i.v. administration, and to 22% (rat) and 35% (dog) after p.o. administration. The major part of the dose is excreted via the feces. The drug is reversibly distributed to the tissues. Similar concentrations appear in the well perfused organs. A brain/plasma concentration ratio of greater than or equal to 1 was found and is a favourable prerequisite for a centrally acting analgesic. Insight in the biotransformation pathways of 14C-flupirtine maleate was obtained by structure determination of urinary metabolites. The urinary radioactivity of the rat consisted practically exclusively of p-fluoro-hippuric acid that is generated by an oxydative metabolic degradation of flupirtine. Dog urine, too, contains this metabolite, however, accompanied by the drug excreted unchanged and by a further metabolite structurally still very similar to flupirtine. The latter metabolite is formed via acetylation of an in vivo hydrolysis product of flupirtine and retains 1/4 of the analgesic potency of flupirtine. Regarding the patterns of excretion and of biotransformation the dog represents an intermediate between rat and man.
Assuntos
Aminopiridinas/metabolismo , Analgésicos/metabolismo , Aminopiridinas/sangue , Analgésicos/sangue , Animais , Bile/metabolismo , Biotransformação , Cães , Fezes/análise , Rim/metabolismo , Cinética , Masculino , Fotometria , Ligação Proteica , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
The pharmacokinetics of naftopidil (R,S)-1-[4-(2-methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2 propanol, CAS 57149-07-2) was studied in rats and dogs using 14C-labeled drug in pharmacodynamically effective doses (oral doses: 5/10 mg/kg and intravenous doses: 1/2.5 mg/kg in rats/dogs, respectively). Naftopidil (14C) was rapidly and in high extent absorbed in rats and dogs after oral administration. The absolute bioavailability of the parent compound amounted to 9% in rats and indicates a high first pass effect to in part pharmacodynamically effective metabolites, as was shown in a previous paper. The parent compound and its 14C-metabolites were widely distributed into the periphery, more pronounced in the rat than in the dog, as indicated from comparison of the volumes of distribution and dose corrected Cmax- and AUC0-infinity-values in plasma. Elimination of radioactivity from plasma occurred in rat and dog in a similar rate. Tissue distribution studies in the rat showed highest peak-concentrations in the gastrointestinal (GI) tract (evaluated with contents) due to the predominant biliary elimination, followed by liver, adrenals, pituitary and Harderian glands, lungs, pancreas, kidneys, adipose tissue, bone marrow, aorta, thyroid and lymph nodes. Radioactivity was eliminated from most of the tissues within the first 168 h. Highest fractions of the dose were detected--apart from the GI-tract--in liver, muscle, skin, blood, and kidneys. After repeated administration to rats, accumulation of radioactivity in the 28 tissues examined did not exceed factor 9 or factor 5 in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anti-Hipertensivos/farmacocinética , Naftalenos/farmacocinética , Piperazinas/farmacocinética , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Bile/metabolismo , Disponibilidade Biológica , Cães , Fezes/química , Feminino , Injeções Intravenosas , Absorção Intestinal , Masculino , Naftalenos/administração & dosagem , Piperazinas/administração & dosagem , Gravidez , Ratos , Ratos Endogâmicos , Distribuição TecidualRESUMO
The metabolism of 14C-naftopidil ((R,S)-1-(2-methoxyphenyl)-1-piperazinyl-3- (1-naphthyl-oxy-2-propanol, CAS 57149-07-2) and the pharmacodynamic action of the metabolites was investigated. The metabolic pathway in rat, dog, mouse and man was qualitatively similar, with preference for the hydroxylation of the phenyl or naphthyl moiety of naftopidil [phenyl)hydroxy-metabolite, (naphthyl)hydroxy-metabolite). Cleavage of the parent compound and production of the propylene glycol metabolite was a further important reaction especially for rat and man. In all species investigated, demethylation of naftopidil occurs to a minor extent. O-desmethyl-naftopidil, (phenyl)hydroxy-naftopidil and (naphthyl)hydroxy-naftopidil were found to have similar affinities for the alpha 1-adrenoceptors as the parent compound (IC50)nmol/l): 433.0; 585.0; 52.7; respectively; naftopidil: 235.0). The naftopidil metabolites, like the parent compound showed no alpha 2- or beta-adrenoceptor affinity.
Assuntos
Naftalenos/farmacocinética , Piperazinas/farmacocinética , Animais , Bile/metabolismo , Biotransformação , Cromatografia em Camada Fina , Cães , Fezes/química , Feminino , Humanos , Masculino , Espectrometria de Massas , Camundongos , Naftalenos/metabolismo , Piperazinas/metabolismo , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/metabolismo , Especificidade da EspécieRESUMO
Single oral doses of the non-opioid, centrally-acting analgesic flupirtine maleate (Katadolon, CAS 75507-68-5) were administered to healthy volunteers and the 2 h plasma levels determined with a new specific HPLC assay. 50, 100, 200, and 300 mg were ingested as the commercial capsules in a double-blind randomized cross-over design with time intervals of at least 6 d. Dose-proportionality was observed for the median 2 h plasma levels which is in agreement with dose-proportionality previously described for multiple-dose studies.
Assuntos
Aminopiridinas/sangue , Analgésicos/sangue , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Método Duplo-Cego , HumanosRESUMO
Biotransformation of 7-(3-[2-(3,5-dihydroxyphenyl)-2-hydroxy-ethylamino]-propyl)-theophylline (reproterol, Bronchospasmin), a beta 2-adrenergic drug recently introduced into therapeutic use, leads to the same main metabolite in animals and in man. By mass-spectroscopy and by synthesis its structure was shown to be tetrahydroisoquinoline derivative which is produced from reproterol by uptake of an additional carbon atom concomitant with cyclization.
Assuntos
Agonistas Adrenérgicos beta/metabolismo , Metaproterenol/análogos & derivados , Teofilina/análogos & derivados , Agonistas Adrenérgicos beta/síntese química , Animais , Bile/metabolismo , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Eletroforese , Espectrometria de Massas , Metaproterenol/síntese química , Metaproterenol/metabolismo , Ratos , Teofilina/síntese química , Teofilina/metabolismoRESUMO
Pharmacokinetics and biotransformation of l-(+)-alpha-(1-[(3,3-di-3-thienylallyl)-amino]-ethyl)-3-benzyl alcohol hydrochloride (tinofedrine hydrochloride, D 8955, Novocebrin) were investigated in rat and dog by means of the 3H-labelled drug. After i.v. administration similar biphasic time courses of the plasma levels are seen in the rat and the dog. The elimination is linear with a half-life of 3.0 and 3.8 h, respectively. After peroral administration 3H-tinofedrine is absorbed much more rapidly by the dog than by the rat. Radioactivity is subsequently eliminated from plasma by both species at nearly identical speed, which corresponds to that after i.v. administration. Quantitative analysis of the organ distribution after i.v. administration in the rat reveals a distinct affinity of 3H-tinofedrine for the lung. All tissue bindings, however, after both routes of administration are reversible. After preoral administration the drug is absorbed nearly quantitatively in the dog and in the rat with 50--63%. Only unchanged tinofedrine can be detected in the blood of the mesenteric veins. Tinofedrine is completely metabolized. In the rat and in the dog three different conjugates are formed, two of which are excreted with the bile. During their way through the intestine they are split again into tinofedrine, which is found in the feces. 3H-Tinofedrine after i.v. and peroral administration is mainly excreted fecally by the rat and the dog. This is caused by the great extent of the biliary excretion of the metabolites.
Assuntos
Álcoois Benzílicos/metabolismo , Compostos de Benzil/metabolismo , Tiofenos/metabolismo , Animais , Biotransformação , Cães , Fezes/análise , Hidrólise , Técnicas In Vitro , Absorção Intestinal , Rim/metabolismo , Cinética , Fígado/metabolismo , Masculino , Ligação Proteica , RatosRESUMO
Investigations on the pharmacokinetics and biotransformation in the rat, dog, rabbit and in humans were performed with 3H-or 14C-labelled 7-(3-[2-(3,5-dihydroxyphenyl)-2-hydroxy-ethlamino]-propyl)-theophylline (reproterol, Bronchospasmin). Following i.v. administration of reproterol, a similar course of the plasma levels as shown in both rat and dog. After oral administration to the rat, elimination occurs within 2 h following application; in the dog, however, a relatively constant plasma level persists for up to 24 h, which is then reduced during an elimination half-life of 12.4 h. Following i.v. as well as oral administration to the rabbit, phases of distribution and elimination persist over a considerable length of time. Plasma levels following oral administration remain relatively constant during a time period of 8--30 h, after which they decrease with a half-life of 70 h. Renal elimination in the dog and rabbit after i.v. application seems to be the main route of excretion (dog 57%, rabbit 66%), while in the rat there is 58% fecal elimination. Absorption ratios following oral administration amount to 13% in the rabbit and 18% in the rat and dog. The absorption ration in the rat following intratracheal application reaches 90%. This was particularly important in view of the anticipated use of reproterol as an aerosol. Tests on the quantitative organic distribution further showed that in the rat, the lund tissue has a particular affinity to reproterol. In man following i.v. administration, reproterol is rapidly distributed and eliminated. The highest plasma level reached within 2 h after oral administration, correlates well with the initial plasma level following i.v. administration. A great similarity was shown for the reproterol metabolism in rat, dog, rabbit and man. With complete metabolization, the same main metabolite is always formed.
Assuntos
Broncodilatadores/metabolismo , Fenetilaminas/metabolismo , Xantinas/metabolismo , Administração Oral , Animais , Biotransformação , Broncodilatadores/administração & dosagem , Fenômenos Químicos , Química , Cromatografia em Camada Fina , Cães , Humanos , Injeções Intravenosas , Intubação Intratraqueal , Cinética , Fenetilaminas/administração & dosagem , Coelhos , Ratos , Xantinas/administração & dosagemRESUMO
Serum concentrations of theophylline and etofylline were analysed by a specific HPLC-method in 6 volunteers after i.v. and p.o. administration of the cardiotonic Cordalin ampoules, drops and dragees. Maximum serum concentrations were reached by theophylline an etofylline at about the same time: 1.0-1.2 h after Cordalin drops; 2.3-2.6 h after Cordalin dragees. The half-life of serum elimination was 5.0-7.2 h for theophylline and 5.5-6.9 h for etofylline. The absolute bioavailability of the two oral formulations was calculated from the areas under the serum curves. For theophylline it is complete from the dragees and 78% from drops. Etofylline, too, is highly bioavailable: 94% from the dragees, 84% from drops. From the kinetic data the conclusion can be drawn that accumulation of theophylline and etofylline will be negligible after Cordalin if administered according to prescribed directions.
Assuntos
Cardiotônicos/metabolismo , Teofilina/análogos & derivados , Teofilina/sangue , Administração Oral , Disponibilidade Biológica , Cardiotônicos/administração & dosagem , Combinação de Medicamentos , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Cinética , Masculino , Pessoa de Meia-Idade , Teofilina/administração & dosagemRESUMO
The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.
Assuntos
Carbocisteína/metabolismo , Cisteína/análogos & derivados , Adulto , Disponibilidade Biológica , Cápsulas , Carbocisteína/administração & dosagem , Cromatografia Gasosa , Feminino , Humanos , Cinética , Masculino , PósRESUMO
1. Flupirtine is a novel and, in all probability, centrally acting, analgesic. The present investigation was conducted in order to investigate dose-related effects of perorally administered flupirtine in man, with special regard to specifically analgesic actions, employing a model based on pain-related chemosomatosensory evoked potentials and subjective intensity estimates of painful stimuli. 2. Plasma concentrations of flupirtine measured 2 h after dosing linearly increased as a function of the administered dose. 3. It was possible to reproduce our own previously obtained results, which established the analgesic action of 200 mg flupirtine administered perorally. 4. Intensity estimates linearly decreased as a function of the administered dose, whereas chemosomatosensory evoked potential amplitudes non-linearly changed in relation to the administered dose. 5. In the spontaneous EEG, a dose-dependent increment in the power-spectra was observed, and this mainly in the alpha- and beta-range.
Assuntos
Aminopiridinas/farmacologia , Analgesia , Analgésicos/farmacologia , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Administração Oral , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Analgésicos/administração & dosagem , Analgésicos/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletroencefalografia , Feminino , Humanos , Masculino , Desempenho Psicomotor/efeitos dos fármacosRESUMO
Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.