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1.
Yakugaku Zasshi ; 130(4): 613-20, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20372009

ABSTRACT

We established a method for estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, using the free fraction of drug in plasma (fu), serum protein level (P), liver volume (LV), and CYP activity (Vmax/Km) as indices of physiological and biochemical development in children up to 15 years old. This method allows the child/adult dose ratio (D(C)/D(A))=child/adult oral clearance ratio (CL((PO)(C))/CL((PO)(A))) of drugs mainly metabolized in the liver to be estimated by the following equation: [formula: see text]. Major metabolism of drugs was ascribed to CYP1A2 for theophylline and caffeine, and CYP1A2 and CYP2D6 for propranolol and mexiletine. For theophylline and caffeine, CL((PO)(C))/CL((PO)(A)) calculated from the child/adult body surface area ratio (BSA ratio) and the value calculated by our method were compared, using CL((PO)(C))/CL((PO)(A)) calculated from the clearance ratio based on population pharmacokinetics (PPK ratio) as a reference. For all drugs, pediatric doses calculated from the Crawford equation and our equation were compared, with predetermined doses as the reference. For theophylline and caffeine, the relative accuracy of our method was significantly higher than that of BSA-based estimation when the PPK ratio was used for reference. For theophylline, caffeine, and propranolol, the relative accuracy of our method was significantly higher than that of BSA-based estimation when predetermined doses were used for reference. These findings indicate the validity of our method which considers the physiological and biochemical development (i.e., fu, P, LV, and CYP activity) for pediatric dose estimation.


Subject(s)
Blood Proteins/metabolism , Cytochrome P-450 Enzyme System/physiology , Isoenzymes/physiology , Liver/growth & development , Liver/metabolism , Pharmaceutical Preparations/metabolism , Adolescent , Child, Preschool , Humans , Infant , Liver/enzymology , Metabolic Clearance Rate , Pharmacokinetics
2.
Eur J Pharm Biopharm ; 73(2): 247-52, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19560537

ABSTRACT

The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C(max) both increased by about 2-fold with 100mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3 w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50 nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral formulations across an artificial membrane were not significantly different. The C(max) and AUC(0-infinity) of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (F(r)) of DHA-ME in comparison to Neoral was determined to be 114%, while the F(r) of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability.


Subject(s)
Cyclosporine/pharmacokinetics , Docosahexaenoic Acids/chemistry , Excipients/chemistry , Immunosuppressive Agents/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Chemistry, Pharmaceutical , Cyclosporine/administration & dosage , Cyclosporine/blood , Cyclosporine/chemistry , Drug Compounding , Drug Stability , Emulsions , Ethanol/chemistry , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Immunosuppressive Agents/chemistry , Male , Membranes, Artificial , Models, Biological , Particle Size , Permeability , Polysorbates/chemistry , Rats , Rats, Wistar
3.
Int J Pharm ; 361(1-2): 251-2, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18577438

ABSTRACT

We recently reported that docosahexaenoic acid (DHA) enhanced the bioavailability of cyclosporine A (CsA) in a conventional oil formulation by inhibiting CYP3A-mediated gut metabolism. The aim of this study was to evaluate the effect of ethyl docosahexaenoate (DHA-EE), the commercially available form of DHA, on the absorption of CsA from its microemulsion formulation, Neoral, in rats. AUC(infinity), AUC(0-10h) and C(max) of CsA decreased significantly when DHA-EE was co-administered, indicating that CsA absorption was diminished by DHA-EE. The results using a laser nanoparticle size analyzer exhibited approximately 60-fold shifting of the microemulsoin particle size from 0.042 microm to 2.46 microm, when 1mg/ml DHA-EE was added to the microemulsion solution in vitro. Considering that the absorption of microemulsified drugs may decrease with increase in the particle size, the observed pharmacokinetics change of CsA may be caused by microemulsion enlargement, due to physicochemical interactions with DHA-EE. Possible interactions between DHA-EE and emulsified drugs might be of clinical importance.


Subject(s)
Cyclosporine/pharmacokinetics , Docosahexaenoic Acids/pharmacology , Emulsions/chemistry , Immunosuppressive Agents/pharmacokinetics , Administration, Oral , Animals , Cyclosporine/administration & dosage , Docosahexaenoic Acids/administration & dosage , Drug Interactions , Immunosuppressive Agents/administration & dosage , Lasers , Male , Nanoparticles/chemistry , Particle Size , Rats , Rats, Wistar
4.
Biol Pharm Bull ; 30(8): 1586-8, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17666827

ABSTRACT

This study was conducted to investigate the inhibitory effects of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) on cytochrome P450 3A (CYP3A). The inhibition of 6beta-hydroxy testosterone formation from testosterone in rat liver microsomes was used as an index of CYP3A activity. In the present study, among the three types of fatty acids, the rank order of inhibitory effects of fatty acids was SFAs

Subject(s)
Cytochrome P-450 CYP3A/metabolism , Fatty Acids, Unsaturated/pharmacology , Fatty Acids/pharmacology , Microsomes, Liver/enzymology , Animals , Male , Microsomes, Liver/drug effects , Rats , Rats, Wistar , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , Testosterone/metabolism
5.
J Pharm Pharmacol ; 58(5): 651-8, 2006 May.
Article in English | MEDLINE | ID: mdl-16640834

ABSTRACT

This study investigated the effect of docosahexaenoic acid (DHA) on the metabolism of saquinavir by cytochrome P450 3A (CYP3A) in-vitro using rat liver microsomes and in-vivo using rats. DHA showed a concentration-dependent inhibition of in-vitro saquinavir metabolism with Km, Vmax and Ki values of 2.21 microM, 0.054 micromol h(-1) (mg protein)(-1) and 149.6 microM, respectively. After oral co-administration with 250 microg kg(-1) DHA, the bioavailability of saquinavir significantly increased approximately 4 fold (P < 0.01) without affecting the elimination half-life, as compared with the control. In contrast, oral administration of DHA did not affect the kinetic parameters of saquinavir administered intravenously. These results suggest that the inhibitory effect of DHA on saquinavir metabolism predominantly takes place in the gut and imply that DHA impairs the function of enteric, but not of hepatic, CYP3A. The pharmacokinetic interaction occurred only when DHA was taken simultaneously with oral administration of saquinavir. These results considered together with the lack of time-dependent saquinavir metabolism inactivation effects in-vitro, imply that the inhibitory effect of DHA is primarily reversible. It is concluded that DHA inhibited saquinavir metabolism in-vitro and enhanced the oral bioavailability of saquinavir in rats.


Subject(s)
Cytochrome P-450 CYP3A Inhibitors , Docosahexaenoic Acids/pharmacology , HIV Protease Inhibitors/metabolism , Microsomes, Liver/drug effects , Saquinavir/metabolism , Administration, Oral , Animals , Biological Availability , Docosahexaenoic Acids/administration & dosage , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , HIV Protease Inhibitors/pharmacokinetics , In Vitro Techniques , Injections, Intravenous , Intestinal Mucosa/metabolism , Intestines/drug effects , Male , Microsomes, Liver/metabolism , Rats , Rats, Wistar , Saquinavir/administration & dosage , Saquinavir/pharmacokinetics
6.
J Ethnopharmacol ; 103(2): 252-60, 2006 Jan 16.
Article in English | MEDLINE | ID: mdl-16213683

ABSTRACT

The present study was designed to investigate the hypolipidemic effects and antioxidant effects of Hibiscus sabdariffa L. (roselle) with regard to protection of LDL oxidation in vivo and ex vivo in rats made hypercholesterolemic by continuous cholesterol feeding. Administering the dried calyx extracts of roselle at doses of 500 and 1,000 mg/kg together with continuous cholesterol feeding to hypercholesterolemic rats for 6 weeks significantly decreased serum cholesterol level by 22% and 26%, respectively (p<0.001); serum triglycerides level by 33% and 28%, respectively (p<0.05); serum LDL level by 22% and 32%, respectively (p<0.05). However, serum HDL level was not affected. LDL was extracted from plasma of the hypercholesterolemic rats and the effects of the dried calyx extracts of roselle on the oxidation of LDL in vivo and ex vivo were examined. Six-week treatment with 250, 500 and 1,000 mg/kg of the extracts significantly decreased thiobarbituric acid reactive substances (TBARs) formation (p<0.05) while the formation of conjugated dienes during the oxidation of LDL induced by CuSO(4) was reduced, but not significantly different. These lines of evidence suggest that the aqueous extracts from the dried calyx of roselle possess both antioxidant effects against LDL oxidation and hypolipidemic effects in vivo. However, its mechanism(s) of action remains to be elucidated.


Subject(s)
Anticholesteremic Agents/therapeutic use , Antioxidants/therapeutic use , Hibiscus , Hypercholesterolemia/drug therapy , Lipoproteins, LDL/drug effects , Phytotherapy , Plant Extracts/therapeutic use , Animals , Anticholesteremic Agents/isolation & purification , Antioxidants/isolation & purification , Lipoproteins, LDL/metabolism , Male , Oxidation-Reduction/drug effects , Plant Extracts/isolation & purification , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/metabolism
7.
Drug Metab Dispos ; 34(2): 305-10, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16299163

ABSTRACT

To investigate the pharmacokinetic interaction between cyclosporin A (CsA) and docosahexaenoic acid (DHA) in vivo, 5 mg/kg CsA was orally or intravenously coadministered with DHA (50-200 microg/kg) to rats. The effect of DHA on CYP3A activity was determined using rat liver microsomes in vitro. Moreover, the effect of DHA on P-glycoprotein (P-gp) function was examined using cultured Caco-2 cells in vitro. After oral coadministration of CsA with 100 microg/kg and 200 microg/kg DHA, bioavailability (BA) was significantly increased, compared with control rats. In contrast, no pharmacokinetic interaction was observed when CsA was intravenously administered in rats dosed orally with DHA, suggesting that DHA did not affect hepatic metabolism. The formation of 6beta-hydroxytestosterone from testosterone in rat liver microsomes was competitively inhibited by DHA. The Km, Vmax, and Ki values were 25.5 microM, 2.45 nmol/min/mg protein, and 5.52 microM, respectively. Moreover, basal-to-apical transport of [3H]CsA in the Caco-2 cell monolayer was not affected by DHA but was decreased by valspodar (PSC 833), a P-gp inhibitor. Our finding is the first to indicate that DHA inhibits intestinal CYP3A both in vitro and in vivo, but not P-gp. It was thus demonstrated that DHA could be used as a BA enhancer for the drugs that are extensively metabolized by CYP3A in the gut.


Subject(s)
Cyclosporine/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors , Docosahexaenoic Acids/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Biological Availability , Caco-2 Cells , Cyclosporine/blood , Cytochrome P-450 CYP3A/metabolism , Humans , Hydroxytestosterones/metabolism , Intestinal Mucosa/metabolism , Male , Microsomes, Liver/metabolism , Rats , Rats, Wistar
8.
Biol Pharm Bull ; 28(3): 481-4, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15744073

ABSTRACT

The present study quantitatively investigated the antioxidant effects of the aqueous extracts from dried calyx of Hibiscus sabdariffa LINN. (roselle) in vitro using rat low-density lipoprotein (LDL). Formations of the conjugated dienes and thiobarbituric acid reactive substances (TBARs) were monitored as markers of the early and later stages of the oxidation of LDL, respectively. Thus, we demonstrated that the dried calyx extracts of roselle exhibits strong antioxidant activity in Cu(2+)-mediated oxidation of LDL (p<0.05) in vitro. The inhibitory effect of the extracts on LDL oxidation was dose-dependent at concentrations ranging from 0.1 to 5 mg/ml. Moreover, 5 mg/ml of roselle inhibited TBARs-formation with greater potency than 100 microM of vitamin E. In conclusion, this study provides a quantitative insight into the potent antioxidant effect of roselle in vitro.


Subject(s)
Antioxidants/pharmacology , Cholesterol, LDL/metabolism , Hibiscus , Animals , Antioxidants/isolation & purification , Dose-Response Relationship, Drug , Male , Plant Components, Aerial , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Thiobarbituric Acid Reactive Substances/metabolism , Water
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