Disposition and metabolism of [3H]gliclazide in rats

Miyazaki, Hisashi; Fujii, Toshihiko; Yoshida, Kōji; Arakawa, Satoshi; Furukawa, Hideo; Suzuki, Hirosato; Kagemoto, Akira; Hashimoto, Masahisa; Tamaki, Nanaya

doi:10.1007/bf03188737

Cited by 27 publications

(15 citation statements)

References 8 publications

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“…The dose of olanzapine is selected by human therapeutic dose extrapolated to rats basing on the body surface area. The gliclazide produced biphasic response in rat model may be due to its enterohepatic circulation in rats [29] [30] and in humans [31]. The selected dose of olanzapine produced a slight reduction in the blood glucose levels which was found to be insignificant.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic and Pharmacokinetic Drug Interaction Of Gliclazide and Olanzapine in Animal Models

K¹

2011

iosrphr

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Studies were conducted in normal rats, alloxan induced diabetic rats and normal rabbits with oral administration of selected doses of gliclazide, olanzapine and their combination with adequate wash out periods in between treatments. Blood samples were collected from rats and rabbits at regular intervals of time and were analysed for glucose by GOD/POD method and for gliclazide by HPLC method. Glicazide produced hypoglycemia and antihyperglycemia in normal/diabetic rats with peak activity at 1h & 8h and 3h & 10 h respectively and in rabbits at 2 h. Therapeutic dose of olanzapine alone did not alter the normal blood glucose level and it did not alter the hypoglycemic response produced by gliclazide in combination. The same phenomenon observed in diabetic rats and rabbits also. There was no significant change in the serum levels and pharmacokinetic parameters of gliclazide when given in combination with olanzapine in normal rabbits. Hence it is concluded that single dose treatment with olanzapine has no influence on pharmacodynamics/ pharmacokinetics of gliclazide. Since the combination was found to be safe in two dissimilar species, the combination might be safe in humans also.Keywords:-Drug interactions, Gliclazide, Olanzapine, Pharmacodynamics and Pharmacokinetics. Introduction:Now a days use of more than one drug (Polypharmacy) is a common practice to treat the chronic disorders like diabetes mellitus, hypertension etc. Polypharmacy is quite common practice all over the world to treat single disorder and multiple disorders which occur simultaneously. In such a situation one drug may interact with other drug leading to drug drug interactions. These interactions are more serious with high risk disorders like diabetes, hypertension or high risk drugs like antidiabetic, antihypertensive, antiarrhythmic drugs etc.Diabetes mellitus is one such disorder which requires careful management of its therapy with respect to blood glucose levels. There are reports for the development of diabetes mellitus in patients with CNS disorders like depression and schizophrenia [1] [2]. In such situations there is every possibility for the use of multiple drug therapy i.e; anti diabetic drugs with drugs for the treatment of other associated disorders and these situations may lead to drug-drug interaction problems. Maintenance of normal blood glucose levels is essential in diabetes since a decrease in blood glucose levels (hypoglycemia) or increase in blood glucose levels (hyperglycemia) is unwanted phenomenon. Hence monitoring of anti diabetic drug therapy in presence of other drugs is very much needed in order to maintain the safety.There are several reports that prevalence of type II diabetes in people with schizophrenia may be 2-4times higher than general population

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamic and Pharmacokinetic Drug Interaction Of Gliclazide and Olanzapine in Animal Models

K¹

2011

iosrphr

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“…The direct glucuronidation metabolite (glucuronidation of hydroxy group bound to the piperidine ring) was formed by rat and human hepatocytes but was not observed in dog hepatocytes. In humans the direct glucuronidation metabolite of haloperidol has been shown to be a major metabolite (Oida et al, 1989;Someya et al, 1992), and direct glucuronidation is also a major metabolic pathway in rats (Miyazaki et al, 1986). Minor metabolites in the hepatocytes were tentatively assigned as hydroxylations, N-oxides and another, earlier eluting, glucuronidation metabolite (ϩOHϩGluc).…”

Section: Resultsmentioning

confidence: 99%

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol.Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...

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“…The gliclazide produced biphasic response in rat model may be due to its enterohepatic circulation in rats [13,14] and in humans [15]. Such effect is not seen in rabbit model.…”

Section: Discussionmentioning

confidence: 99%

Drug-Drug Interaction between Pravastatin and Gliclazide in Animal Models

Satyanarayana

Chandrasekhar²,

Gouda

et al. 2008

Scholarly Research Exchange

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The present study is planned to evaluate the safety of gliclazide (antidiabetic) therapy in the presence of pravastatin (antihyperlipidemic) in rats and rabbits. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide, pravastatin, and their combination. Similarly, studies in normal rabbits were conducted with oral doses of gliclazide, pravastatin, and their combination with adequate washout periods in between the treatments. Blood samples were collected from rats and rabbits at different time intervals and were analyzed for blood serum gliclazide levels. Gliclazide produced hypoglycaemic/antihyperglycaemic activity in normal and diabetic rats with peak activity after 2 hours and 8 hours and hypoglycaemic activity in normal rabbits with peak activity after 3 hours. Pravastatin alone produced minor reduction in blood glucose levels in normal rats/diabetic rats/normal rabbits. Pravastatin increased the hypoglycaemic effect of gliclazide in normal rats/diabetic rats/normal rabbits when administered together. The serum insulin levels were increased with pravastatin treatment in rabbits. The serum gliclazide levels and pharmacokinetic parameters of gliclazide were altered significantly in presence of pravastatin in rabbits. The interaction observed appears to be pharmacokinetic interaction at metabolic and excretion levels.

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Disposition and metabolism of [3H]gliclazide in rats

Cited by 27 publications

References 8 publications

Pharmacodynamic and Pharmacokinetic Drug Interaction Of Gliclazide and Olanzapine in Animal Models

Pharmacodynamic and Pharmacokinetic Drug Interaction Of Gliclazide and Olanzapine in Animal Models

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Drug-Drug Interaction between Pravastatin and Gliclazide in Animal Models

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