RESUMO
1.Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1-8 mg/kg) or CRD (1.1-4.5 mg/kg) and their equivalent dose of DA-9701 to rats. 2. Dose-proportional AUC and dose-independent clearance (10.3-12.1 ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478-0.899%). 3. CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5 mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.
Assuntos
Alcaloides de Berberina/farmacocinética , Ácido Clorogênico/farmacocinética , Preparações de Plantas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Alcaloides de Berberina/metabolismo , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Ácido Clorogênico/metabolismo , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/farmacocinética , Injeções Intravenosas , Masculino , Preparações de Plantas/administração & dosagem , Ratos Sprague-DawleyRESUMO
Hydrochlorothiazide (HCTZ) is used to treat uncomplicated hypertension. However, many studies have reported the variance of inter-individual response to HCTZ. A meta-analysis of published data was conducted to evaluate the pharmacogenetic associations of ACE I/D and ADD1 Gly460Trp polymorphisms with blood pressure changes during HCTZ therapy. To analyze the influence of ACE I/D polymorphism, 4 studies including 1,439 patients were assessed and the 3 genotypes were compared (II vs. ID, II vs. DD, and ID vs. DD) with respect to blood pressure changes. A significant association between ACE and blood pressure change was observed for the comparison of the II and DD (standard differences in means = 0.256; 95% CI, 0.109 - 0.403). For ADD1 Gly460Trp polymorphism, 4 studies including 1,001 patients were assessed, and GlyGly vs. GlyTrp, GlyGly vs. TrpTrp and GlyTrp vs. TrpTrp genotype comparisons were analyzed. A significant association between ADD1 and blood pressure change was observed for the comparisons of GlyGly vs. GlyTrp (standard differences in means= 2.78; 95% CI, 0.563 - 4.99) and GlyGly vs. TrpTrp (standard differences in means = 1.80; 95% CI, 1.38 - 2.22). This study is the first meta-analysis to evaluate the influences of ACE and ADD1 polymorphisms on blood pressure responses to HCTZ to combine the inconsistent results of previous studies.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ligação a Calmodulina/genética , Hidroclorotiazida/farmacologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Genótipo , Humanos , Viés de PublicaçãoRESUMO
1. Since the prevalent hormonal combination therapy with estrogen analogues in cancer patients has frequency and possibility to induce the cholestasis, the frequent combination therapy with 17α-ethynylestradiol (EE, an oral contraceptive) and doxorubicin (an anticancer drug) might be monitored in aspect of efficacy and safety. Doxorubicin is mainly excreted into the bile via P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in hepatobiliary route and metabolized via cytochrome P450 (CYP) 3A subfamily. Also the hepatic Mrp2 (not P-gp) and CYP3A subfamily levels were reduced in EE-induced cholestatic (EEC) rats. Thus, we herein report the pharmacokinetic changes of doxorubicin with respect to the changes in its biliary excretion and hepatic metabolism in EEC rats. 2. The pharmacokinetic study of doxorubicin after intravenous administration of its hydrochloride was conducted along with the investigation of bile flow rate and hepatobiliary excretion of doxorubicin in control and EEC rats. 3. The significantly greater AUC (58.7% increase) of doxorubicin in EEC rats was due to the slower CL (32.9% decrease). The slower CL was due to the reduction of hepatic biliary excretion (67.0% decrease) and hepatic CYP3A subfamily-mediated metabolism (21.9% decrease) of doxorubicin. These results might have broader implications to understand the altered pharmacokinetics and/or pharmacologic effects of doxorubicin via biliary excretion and hepatic metabolism in experimental and clinical estrogen-induced cholestasis.
Assuntos
Bile/metabolismo , Colestase/induzido quimicamente , Doxorrubicina/farmacocinética , Etinilestradiol/efeitos adversos , Fígado/metabolismo , Administração Intravenosa , Animais , Antibióticos Antineoplásicos/farmacocinética , Área Sob a Curva , Colestase/metabolismo , Citocromo P-450 CYP3A/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/metabolismo , Interações Medicamentosas , Etinilestradiol/farmacocinética , Feminino , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Tamoxifen, which is used to treat breast cancer, and ondansetron, used for the treatment of chemotherapy-induced nausea, are commonly metabolized via cytochrome P450 (CYP) 2D subfamily and 3A1/2 in rats, as in humans. This study was conducted to investigate the pharmacokinetic interactions between ondansetron and tamoxifen after intravenous and oral administration of ondansetron (both 8 mg/kg) and/or tamoxifen (2 and 10 mg/kg for intravenous and oral administration, respectively), in rats bearing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammarian tumors (DMBA rats), used as an animal model of human breast cancer. The total area under the plasma concentration-time curve, from time zero to infinity (AUC) of tamoxifen was significantly greater after both intravenous and oral administration with ondansetron, compared to that after administration of tamoxifen-alone. The hepatic and intestinal metabolism of tamoxifen in DMBA rats was inhibited by ondansetron. Taken together, the significant increase in tamoxifen AUC in DMBA rats after intravenous or oral administration with ondansetron may be attributed to non-competitive hepatic (intravenous) and competitive intestinal (oral) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron.
Assuntos
Antieméticos/farmacocinética , Neoplasias Mamárias Experimentais/induzido quimicamente , Ondansetron/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Tamoxifeno/farmacocinética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Administração Oral , Animais , Antieméticos/administração & dosagem , Antieméticos/metabolismo , Área Sob a Curva , Carcinógenos/toxicidade , Interações Medicamentosas , Feminino , Infusões Intravenosas , Neoplasias Mamárias Experimentais/tratamento farmacológico , Ondansetron/administração & dosagem , Ondansetron/metabolismo , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Tamoxifeno/administração & dosagem , Tamoxifeno/metabolismoRESUMO
Etoposide, used for the treatment of breast cancer, is mainly metabolized via hepatic cytochrome P450 (CYP) 3A4 in humans and is also a substrate for p-glycoprotein (P-gp). Morin is known to be able to modulate the activities of metabolic enzymes including CYPs and can act as a potent P-gp inhibitor. The purpose of this study was to investigate the effects of morin on the pharmacokinetics of etoposide in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Etoposide was administered intravenously (2 mg/kg) and orally (10 mg/kg) in control and DMBA rats without (DMBA-WOM) and with (DMBA-WM) morin (15 mg/kg). Protein and mRNA expression of CYP3A and P-gp was analyzed, and the tissue distribution of etoposide was also measured. Both protein and mRNA expression of CYP3A and P-gp was inhibited by morin in the liver, intestine and breast tumors of DMBA-WM rats. After both intravenous and oral administration of etoposide in DMBA-WM rats, the total area under the plasma concentration-time curve from time zero to infinity (AUC) of etoposide was significantly greater, and the time-averaged total body clearance (CL) of etoposide was significantly slower than those in control and DMBA-WOM rats. The amount of etoposide recovered from each tissue was significantly higher in DMBA-WM rats, especially in the breast tumor, liver and large intestine. No significant differences between control and DMBA-WOM rats were observed. Taken together, greater AUC and slower CL of etoposide in DMBA-WM rats could possibly be due to the inhibition of hepatic CYP3A (intravenous) and mainly due to the inhibition of intestinal CYP3A and P-gp (oral) by morin.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacocinética , Etoposídeo/farmacocinética , Flavonoides/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , 9,10-Dimetil-1,2-benzantraceno , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Administração Intravenosa , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/administração & dosagem , Feminino , Expressão Gênica , Fígado/enzimologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacosRESUMO
Protein-calorie malnutrition (PCM) could occur frequently in cancer patients and alter the pharmacokinetics of drugs. Also cysteine shows anti-oxidative effect and changes the activities of drug metabolizing enzyme and/or transporters. Herein, we investigated the effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of tamoxifen were assessed using control, CC (control with cysteine), PCM, PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of tamoxifen were further investigated through in vitro transport studies using rat intestine. The AUCs of intravenous tamoxifen in PCM rats were significantly greater than control rats due to the decrease in the hepatic metabolism via CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels by oral cysteine supplement. The AUC of oral tamoxifen in PCM rats was significantly smaller than in control rats mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of tamoxifen probably via intestinal P-gp inhibition. The present study demonstrated that PCM state and/or oral cysteine supplement had a profound impact on the pharmacokinetics of tamoxifen in rats. If the present rat data are extrapolated to humans, the alterations in tamoxifen absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM and/or oral cysteine supplement.
Assuntos
Cisteína/uso terapêutico , Desnutrição Proteico-Calórica/tratamento farmacológico , Tamoxifeno/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Bile/metabolismo , Transporte Biológico/efeitos dos fármacos , Proteínas Sanguíneas/metabolismo , Cisteína/farmacologia , Diálise , Ingestão de Energia/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Cinética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ligação Proteica/efeitos dos fármacos , Desnutrição Proteico-Calórica/sangue , Ratos , Ratos Sprague-Dawley , Tamoxifeno/administração & dosagem , Tamoxifeno/sangue , Tamoxifeno/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVES: Anti-ulcer drugs are frequently used in patients with acute renal failure (ARF). Zinc acexamate is ionized to zinc and ε-acetamidocaproic acid and free EACA exerts a potent therapeutic effect in treating gastric or duodenal ulcers with few side effects. Thus, pharmacokinetic changes in rats with acute renal failure induced by uranyl nitrate (U-ARF rats) were investigated in this study. METHODS: The in-vivo pharmacokinetics and in-vitro hepatic/intestinal metabolism of EACA were assessed using control and U-ARF rats. The mechanism of urinary excretion of EACA was further investigated in rats. KEY FINDINGS: After intravenous and oral administration of zinc acexamate to U-ARF rats, there were significant increases in the values of the area under the curve (AUC) and decreases in the values for time-averaged renal and nonrenal clearances (Cl(r) and Cl(nr) , respectively) compared with control rats. Slower Cl(nr) was partly due to a decrease in the metabolism in liver and/or intestine. Slower Cl(r) could have been due to urine flow rate-dependent timed-interval renal clearance, decrease in organic anion transporter-mediated renal excretion (drug interaction with probenecid and decrease in the relative contribution of net secretion compared with glomerular filtration in U-ARF rats) and/or impaired kidney function. CONCLUSIONS: The pharmacokinetics were significantly altered in U-ARF rats due to the changes in both the hepatic/intestinal metabolism and urinary excretion.
Assuntos
Injúria Renal Aguda/fisiopatologia , Aminocaproatos , Ácido Aminocaproico/farmacocinética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Administração Oral , Ácido Aminocaproico/administração & dosagem , Animais , Área Sob a Curva , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Infusões Intravenosas , Masculino , Transportadores de Ânions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Nitrato de Uranil/toxicidadeRESUMO
1. The occurrence of cerebral ischemia is prevalent in patients with hypertension and the combination drug therapy is needed. Thus, the pharmacokinetic interaction between metoprolol (anti-hypertension drug) and SP-8203 (a new drug candidate for cerebral ischemia) with respect to the metabolism via CYP isozymes was evaluated. 2. Metoprolol and SP-8203 were administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine in in vivo studies, the disappearance and apparent K(i) of each drug in in vitro microsomes and [I]/K(i) ratios for each drug were determined. In addition, the disappearance of each drug via CYPs in rat and human microsomes were measured. 3. The AUC and CL(NR) of intravenously administered metoprolol with SP-8203 were significantly greater and slower, respectively, than without SP-8203. However, pharmacokinetic parameters of oral metoprolol and intravenous/oral SP-8203 were not altered. 4. The hepatic metabolism of metoprolol via CYP2D was inhibited by SP-8203 in a competitive manner. However, the intestinal metabolism of metoprolol was not influenced by SP-8203. SP-8203 was not metabolized via CYP isozymes in rats and then co-administration of metoprolol did not affect the metabolism of SP-8203.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/enzimologia , Metoprolol/metabolismo , Metoprolol/farmacocinética , Quinazolinonas/farmacocinética , Acetamidas , Administração Intravenosa , Administração Oral , Animais , Baculoviridae , Diálise , Interações Medicamentosas , Humanos , Mucosa Intestinal/metabolismo , Cinética , Fígado/irrigação sanguínea , Masculino , Metoprolol/administração & dosagem , Metoprolol/química , Microssomos Hepáticos/metabolismo , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Quinazolinonas/metabolismo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Fatores de TempoRESUMO
In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10 mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats). The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats. The AUC of norverapamil and AUC(norverapamil)/AUC(verapamil) ratios following intravenous and oral administration of verapamil were unchanged in HL rats. Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.
Assuntos
Hiperlipidemias/patologia , Verapamil/análogos & derivados , Administração Oral , Animais , Proteínas Sanguíneas/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Infusões Intravenosas , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Poloxâmero , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Verapamil/administração & dosagem , Verapamil/sangue , Verapamil/farmacocinéticaRESUMO
The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers. The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC(0-6 h)s of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition. If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.
Assuntos
Cisteína/uso terapêutico , Desnutrição Proteico-Calórica/tratamento farmacológico , Taxoides/farmacocinética , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Análise Química do Sangue , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Docetaxel , Relação Dose-Resposta a Droga , Duodeno/efeitos dos fármacos , Duodeno/metabolismo , Ingestão de Energia/efeitos dos fármacos , Humanos , Injeções Intravenosas , Rim/efeitos dos fármacos , Rim/patologia , Cinética , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Desnutrição Proteico-Calórica/sangue , Desnutrição Proteico-Calórica/urina , Ratos , Ratos Sprague-Dawley , Rodamina 123/metabolismo , Taxoides/administração & dosagem , Taxoides/farmacologia , Fatores de Tempo , Aumento de Peso/efeitos dos fármacosRESUMO
The pharmacokinetics of carbamazepine (CBZ) and its active 10,11-epoxide metabolite (CBZ-E) were evaluated after intravenous and oral administration of 5 mg/kg CBZ to rats with hyperlipidemia induced by poloxamer 407 (HL rats) and controls. The total area under the plasma concentration-time curve (AUC) of CBZ in HL rats after intravenous administration was significantly greater than that in controls due to their slower non-renal clearance (CL(NR)). This was due to slower hepatic CL(int) for metabolism of CBZ to CBZ-E in HL rats via CYP3A1/2. This result was consistent with a previous study indicating reduced hepatic CYP3A1/2 expression in HL rats. Interestingly, the AUC of CBZ-E was also increased in HL rats, while AUC(CBZ-E)/AUC(CBZ) ratios remained unchanged. These results suggested that further metabolism of CBZ-E to the inactive metabolite trans-10,11-dihydoxyl-10,11-dihydro-CBZ (CBZ-D) via microsomal epoxide hydrolase (mEH) was also slowed in HL rats. The significantly reduced hepatic mRNA level and expression of mEH protein in HL rats compared to controls confirmed the above hypothesis. Similar pharmacokinetic changes were observed in HL rats after oral administration of CBZ. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Caution is required regarding pharmacotherapy in the hyperlipidemic state in cases where drugs that are metabolized principally by CYP3A1/2 or mEH and have a narrow therapeutic range are in use.
Assuntos
Analgésicos não Narcóticos/farmacocinética , Carbamazepina/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Epóxido Hidrolases/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Tiofenos/metabolismo , Analgésicos não Narcóticos/sangue , Animais , Proteínas de Arabidopsis , Área Sob a Curva , Carbamazepina/sangue , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Interações Medicamentosas , Epóxido Hidrolases/genética , Hiperlipidemias/induzido quimicamente , Transferases Intramoleculares , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Poloxâmero/toxicidade , Ratos , Ratos Sprague-Dawley , Tensoativos/toxicidade , Fatores de TempoRESUMO
Reliably predicting pharmacokinetic behavior in humans from preclinical data is an important aspect of drug development. The most widely used technique in this regard is allometric scaling. In this review, various approaches developed for predicting pharmacokinetic parameters in humans using interspecies scaling are introduced and discussed. Methods to predict plasma concentration-time profiles in humans after intravenous and oral administration are also reviewed. The reliable prediction of human pharmacokinetics with regard to investigational drugs is aimed, ultimately, at selecting the first in-human dose with which to begin clinical studies. Approaches for the selection of the first in-human dose are also reviewed. Although there have been many trials to compare and optimize interspecies scaling methods, no firm conclusions have been reached. Because interspecies scaling methods are still highly empirical, further effort is needed to improve the reliability of predicting human pharmacokinetics by interspecies scaling.
Assuntos
Drogas em Investigação/farmacocinética , Modelos Biológicos , Animais , Tamanho Corporal , Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Drogas em Investigação/análise , Humanos , Especificidade da EspécieRESUMO
Astaxanthin is a carotenoid with antioxidant, anti-cancer and anti-inflammatory properties. The pharmacokinetics of astaxanthin after its intravenous (5, 10, and 20 mg/kg) and oral (100 and 200 mg/kg) administration and its first-pass extraction ratios after its intravenous, intraportal or intragastric (20 mg/kg) administration were evaluated in rats. The pharmacokinetic parameters of astaxanthin were dose dependent after its intravenous administration, due to the saturable hepatic metabolism of astaxanthin, but dose independent after oral administration. The gastrointestinal absorption of astaxanthin followed the flip-flop model. The hepatic and gastrointestinal first-pass extraction ratios of astaxanthin were approximately 0·490 and 0·901, respectively. Astaxanthin was metabolised primarily by hepatic cytochrome P-450 1A1/2 in rats. Astaxanthin was unstable up to 4 h incubation in four rat gastric juices and up to 24 h incubation in various buffer solutions having a pH of 1-13. The tissue/plasma ratios of astaxanthin at 8 and 24 h after its oral administration (100 mg/kg) were greater than unity for all tissues studied, except in the heart, at 8 h, indicating that the rat tissues studied had high affinity for astaxanthin.
Assuntos
Administração Oral , Animais , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Mucosa Gástrica/metabolismo , Injeções Intravenosas , Fígado/metabolismo , Masculino , Metilcolantreno/farmacologia , Veia Porta , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Xantofilas/administração & dosagem , Xantofilas/metabolismo , Xantofilas/farmacocinéticaRESUMO
Metadoxine [an ion-pair between pyridoxine and pyrrolidone carboxylate (PCA)] plus garlic oil treatment synergistically reduces alcoholic steatosis compared to each agent alone. We evaluated the effect of garlic oil on the pharmacokinetics of pyridoxine. After the oral administration of metadoxine, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and the peak plasma concentration (C(max)) of pyridoxine were significantly greater (by 40.6%) and higher (by 63.9%), respectively, than after oral administration of pyridoxine plus PCA. Oral metadoxine plus garlic oil also gave larger AUC (31.8%) and higher C(max) (64.9%) than pyridoxine plus PCA. However, garlic oil did not change the AUC or C(max) of pyridoxine in metadoxine. Thus, garlic oil does not enhance the metadoxine activity by affecting the absorption of pyridoxine.
Assuntos
Compostos Alílicos/administração & dosagem , Compostos Alílicos/farmacocinética , Piridoxina/administração & dosagem , Piridoxina/farmacocinética , Ácido Pirrolidonocarboxílico/administração & dosagem , Ácido Pirrolidonocarboxílico/farmacocinética , Sulfetos/administração & dosagem , Sulfetos/farmacocinética , Absorção/efeitos dos fármacos , Absorção/fisiologia , Administração Oral , Animais , Combinação de Medicamentos , Interações Medicamentosas/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: This study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite, SK3541, using various hepatic CYP inducers and inhibitors in rats. METHODS: Mirodenafil at a dose of 20 mg/kg was administered intravenously to control rats and rats pretreated with various CYP inducers and inhibitors. The disappearance of SK3541 was also measured in vitro hepatic microsomes of rats with and without CYP inducer and inhibitors. RESULTS: Compared to controls, in rats pretreated with 3-methylcholanthrene, orphenadrine, and dexamethasone (main inducers of CYP1A1/2, 2B1/2, and 3A1/2, respectively), the non-renal clearances (CLNRs) of mirodenafil were significantly faster (by 39.4%, 59.3%, and 63.9%, respectively). However, compared to controls, in rats pretreated with quinine and troleandomycin (main inhibitors of CYP2D subfamily and 3A1/2, respectively), the CLNRs of mirodenafil were significantly slower (by 36.1% and 33.2%, respectively). In rat hepatic microsomes spiked with furafylline, quinine, and troleandomycin (main inhibitors of CYP1A2, 2D subfamily, and 3A1/2, respectively), the intrinsic clearances (CLints) for the disappearance of SK3541 were significantly slower (by 18.4%, 35.3%, and 51.5%, respectively) than controls. Also in rat hepatic microsomes pretreated with orphenadrine (a main inducer of CYP2B1/2), the CLint for the disappearance of SK3541 was significantly faster (by 55.5%) than controls. CONCLUSIONS: The above data suggest that hepatic CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 are involved in the metabolism of both mirodenafil and SK3541 in rats.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Pirimidinonas/metabolismo , Sulfonamidas/metabolismo , Animais , Indução Enzimática , Inibidores Enzimáticos/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Inibidores da Fosfodiesterase 5 , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Tamoxifen and ondansetron were commonly metabolized via rat hepatic CYP2D subfamily and 3A1/2, and ondansetron is used to treat chemotherapy-induced nausea. The purpose of this study was to report the pharmacokinetic interaction between tamoxifen and ondansetron in rats. METHODS: The pharmacokinetics of tamoxifen and ondansetron were evaluated after the intravenous and oral administration of tamoxifen, ondansetron, and both drugs together to rats. The Vmax (maximum velocity), Km (apparent Michaelis-Menten constant), CLint (intrinsic clearance), Ki (inhibition constant), and [I] (concentration of inhibitor in the liver and intestine)/Ki ratio of ondansetron were also measured. RESULTS: The AUC0-infinitys of tamoxifen were significantly greater after both intravenous and oral administration with ondansetron compared to those of tamoxifen alone. The significantly slower hepatic and intestinal CLints for the disappearance of tamoxifen with both drugs together were due to inhibition of metabolism of tamoxifen by ondansetron via CYP2D subfamily and 3A1/2. CONCLUSIONS: The significantly greater AUC0-infinity of tamoxifen after the intravenous administration of both drugs together could have possibly been attributable to a non-competitive (hepatic) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron. The significantly greater AUC0-infinity of tamoxifen after the oral administration of both drugs together could have been attributable to a competitive (intestinal) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron in addition to non-competitive inhibition in the liver.
Assuntos
Oxirredutases do Álcool/metabolismo , Hidrocarboneto de Aril Hidroxilases/metabolismo , Proteínas de Membrana/metabolismo , Ondansetron/farmacocinética , Tamoxifeno/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A , Família 2 do Citocromo P450 , Interações Medicamentosas , Infusões Intravenosas , Mucosa Intestinal/metabolismo , Cinética , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Microssomos/metabolismo , Ondansetron/administração & dosagem , Ondansetron/metabolismo , Ratos , Ratos Sprague-Dawley , Tamoxifeno/administração & dosagem , Tamoxifeno/metabolismoRESUMO
Iron-overload disorders cause hepatocyte injury and inflammation by oxidative stress, possibly leading to liver fibrosis and hepatocellular carcinoma. This study investigated the efficacy of sauchinone, a bioactive lignan, in preventing iron-induced liver injury and explored the mechanism of sauchinone's activity. To create iron overload, mice were injected with phenylhydrazine, and the effects on hepatic iron and histopathology were assessed. Phenylhydrazine treatment promoted liver iron accumulation and ferritin expression, causing hepatocyte death and increased plasma arachidonic acid (AA). Sauchinone attenuated liver injury (EC(50)=10 mg/kg) and activated AMPK in mice. Treatment of hepatocytes with iron and AA simulated iron overload conditions: iron + AA synergistically amplified cytotoxicity, increasing H(2)O(2) and the mitochondrial permeability transition. Sauchinone protected hepatocytes from iron + AA-induced cytotoxicity, preventing the induction of mitochondrial dysfunction and apoptosis (EC(50)=1 microM), similar to the result using metformin. Sauchinone treatment activated LKB1, which led to AMPK activation: these events contributed to cell survival. Evidence of cytoprotection by LKB1 and AMPK activation was revealed in the reversal of sauchinone's restoration of the mitochondrial membrane potential by either dominant negative mutant AMPKalpha or chemical inhibitor. In conclusion, sauchinone protects the liver from toxicity induced by iron accumulation, and sauchinone's effects may be mediated by LKB1-dependent AMPK activation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzopiranos/farmacologia , Dioxóis/farmacologia , Ferro/toxicidade , Lignanas/farmacologia , Fígado/efeitos dos fármacos , Fígado/lesões , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Araquidônico/farmacologia , Benzopiranos/química , Dioxóis/química , Ativação Enzimática/efeitos dos fármacos , Ferro/administração & dosagem , Lignanas/química , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fenil-Hidrazinas/farmacologia , Saururaceae/químicaRESUMO
Comprehensive studies support the notion that oltipraz [4-methyl-5-(2-pyrazynyl)-1,2-dithiole-3-thione] and its congeners exert cancer chemopreventive effects by the prevention, inhibition or reversal of carcinogenic processes. Recently, it was found that dithiolethione compounds had the activities to prevent or treat fibrosis, insulin resistance, and mitochondrial protective effects in the liver by a mechanism involving AMP-activated protein kinase (AMPK) and/or 70-kDa ribosomal protein S6 kinase 1 (S6K1). Moreover, chemical regulation of the AMPK-S6K1 pathway was found to affect Liver X receptor (LXR) activity and lipogenesis, leading to the identification of AMPK and S6K1 as targets for treating hepatic steatosis. These biological activities of dithiolethiones may offer a novel approach to pharmaceutical intervention. This review focuses on the interaction between oltipraz and the AMPK-mTOR-S6K1 pathway, which regulates genes that confer hepatocyte protection from intoxication, disrupted energy metabolism, and inflammation. In terms of therapeutic potential, the findings reviewed here demonstrate a new therapeutic potential for dithiolethiones, which function in a unique manner, and offer the possibility of new treatments for hepatic diseases.
Assuntos
Hepatopatias/tratamento farmacológico , Pirazinas/uso terapêutico , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Fígado Gorduroso/prevenção & controle , Glutationa Transferase/fisiologia , Humanos , Inativação Metabólica , Resistência à Insulina , Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Quinases/fisiologia , Pirazinas/farmacocinética , Pirazinas/farmacologia , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR , Tionas , TiofenosRESUMO
PURPOSE: To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague-Dawley rats. METHODS: Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats. RESULTS: The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CL NR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable. CONCLUSIONS: After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC 0-12 h) of unconjugated, conjugated, and total silibinin were comparable.
Assuntos
Pirazinas/farmacocinética , Ratos Sprague-Dawley , Silimarina/farmacocinética , Administração Oral , Animais , Anticarcinógenos , Área Sob a Curva , Interações Medicamentosas , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Ratos , Silibina , Silimarina/administração & dosagem , Silimarina/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Tionas , Tiofenos , Distribuição TecidualRESUMO
Liquiritigenin (LQ), an active component of licorice, has an inhibitory effect on LPS-induced inhibitory nitric oxide synthase expression. This study investigated the effects of LQ on choleresis, the expression of hepatic transporters and phase-II enzymes, and fulminant hepatitis. The choleretic effect and the pharmacokinetics of LQ and its glucuronides were monitored in rats. After intravenous administration of LQ, the total area under the plasma concentration-time curve of glucuronyl metabolites was greater than that of LQ in plasma, which accompanied elevations in bile flow rate and biliary excretion of bile acid, glutathione, and bilirubin. The expressions of hepatocellular transporters and phase-II enzymes were assessed by immunoblots, real-time PCR, and immunohistochemistry. In the livers of rats treated with LQ, the protein and mRNA levels of multidrug resistance protein 2 and bile salt export pump were increased in the liver, which was verified by their increased localizations in canalicular membrane. In addition, LQ treatment enhanced the expression levels of major hepatic phase-II enzymes. Consistent with these results, LQ treatments attenuated galactosamine/LPS-induced hepatitis in rats, as supported by decreases in the plasma alanine aminotransferase, liver necrosis, and plasma TNF-alpha. These results demonstrate that LQ has a choleretic effect and the ability to induce transporters and phase-II enzymes in the liver, which may be associated with a hepatoprotective effect against galactosamine/LPS. Our findings may provide insight into understanding the action of LQ and its therapeutic use for liver disease.