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PubMed1999

A preliminary investigation of the possible hypoglycemic activity of Hibiscus rosa-sinensis.

The hypoglycemic activity of an ethanol extract of Hibiscus rosa-sinensis was studied in glucose located rats. After a single dose of the extract, a slight but insignificant hypoglycemic effect was observed at 30 and 90 min. At 120 min it was mild but significant. After repeated administration of the extract (once a day for seven consecutive days) a statistically significant (P < 0.001) reduction in blood glucose levels was observed at 30, 90 and 120 min after glucose loading. The average hypoglycemic activity, after repeated administration of 250 mg kg-1 leaf extract was 81%, under similar conditions average activity of tolbutamide was 96%. At 250 mg.kg-1 the efficacy of the extract was found to be 84% of tolbutamide (100 mg.kg-1). Repeated treatment of animals either with tolbutamide a sulphonylurea or H. rosa-sinensis caused a 2-3-fold improvement in glucose tolerance as compared to those receiving only once. These data suggest that the leaf extract acts like tolbutamide and the mechanism of action may be a stimulation of pancreatic beta cells to produce more insulin or an increase of the glycogen deposition in liver. It appears that the active principle in the tested extract has the sulphonylurea skeleton in which-SO2-NH-CO-group and the substituents (S1 and S2) may be the possible active sites responsible for its hypoglycemic activity.

Animals↗
PubMed2002

Evaluation of the hypoglycemic and anti-oxidant activities of Morinda officinalis in streptozotocin-induced diabetic rats.

AIM OF STUDY: The aim was to investigate the hypoglycemic and anti-oxidant activities of the dried roots of Morinda officinalis in streptozotocin-induced diabetic rats. METHODOLOGY: An ethanolic extract of the dried roots of Morinda officinalis and its three fractions (ethyl acetate, n-butanol and water) were obtained. We evaluated the hypoglycemic effects of three different single doses of the crude extract and its fractions in normal and diabetic rats for three hours after administration. Administration of the extract at 150 mg/kg twice daily for 10 days to the diabetic rats was also carried out. The effects of the 10-day treatment on the fasting serum glucose, insulin, total cholesterol, triglycerides, body weight, food intake, fluid intake, hepatic superoxide dismutase (SOD), catalase (CAT) activities, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and renal TBARS levels were monitored. RESULTS: In the three-hour dose response study, the crude ethanolic extract reduced the fasting serum glucose levels of the diabetic rats significantly at 150 mg/kg but increased those of the normal rats significantly at 600 mg/kg only. The water fraction demonstrated a dose dependent hypoglycemic effect in the diabetic rats whereas the n-butanol fraction increased the fasting serum glucose levels of the diabetic rats significantly at 50 mg/kg only within three hours after administration. The 10-day oral administration of the extract reduced the fasting serum glucose, hepatic and renal TBARS level and significantly increased the hepatic SOD and CAT activities as well as GSH levels. CONCLUSION: The results indicate that the dried roots of Morinda officinalis possess hypoglycemic, hyperglycemic and anti-oxidant properties.

Animals↗
PubMedDate not supplied

[Pharmacologic interactions between quinolones and oral hypoglycemic agents. An experimental study on rabbits].

The association between antibiotics and oral hypoglycemic agents can determine various pharmacological interactions. The aim of our work has been to verify experimentally the eventual pharmacological interactions that may occur when some quinolones (nalidixic acid, ofloxacin, pefloxacin and sparfloxacin) are administered in association with oral hypoglycemic drugs (phenphormine and glibenclamide). Our results showed that ofloxacin, pefloxacin and sparfloxacin only at high dosages (not used in the human clinic) can increase the phenphormine and glibenclamide hypoglycemic effect. The nalidixic acid, just at therapeutic doses, is able to increase the hypoglycemic effect of the drugs studied.

Animals↗
PubMed2004

Starting insulin in type 2 diabetes: continue oral hypoglycemic agents? A randomized trial in primary care.

OBJECTIVE: To evaluate the effects of insulin 30/70 twice daily or bedtime isophane (NPH) insulin plus continued sulfonylurea and metformin in patients with type 2 diabetes in primary care. STUDY DESIGN: Open-label, randomized trial. POPULATION: Persons younger than 76 years with type 2 diabetes whose disease had not been controlled with oral hypoglycemic agents alone. A total of 64 insulin-naive patients treated with maximal feasible dosages of sulfonylurea and metformin (baseline glycosylated hemoglobin [HbA1c]=8.5%) were randomly assigned to insulin monotherapy (IM group; n=31) or insulin in addition to unchanged oral hypoglycemic medication (IC group; n=33) for 12 months. Insulin doses were adjusted to obtain fasting glucose <7.0 mmol/L and postprandial glucose <10.0 mmol/L. OUTCOMES MEASURED: Outcome measures included HbA1c, treatment failure, weight, hypoglycemic events and symptoms, satisfaction with treatment, general well-being, and fear of injecting insulin and testing. RESULTS: HbA1c improved from 8.3% to 7.6% in the IC group, and from 8.8% to 7.6% in the IM group (P=NS). The IC group had 24% treatment failures, compared with 2% in the IM group (P=.09). Patients in the IC group had less weight gain than those in the IM group (1.3 vs 4.2 kg; P=.01), and they reported fewer hypoglycemic events (2.7 vs 4.3; P=.02). Increased satisfaction with treatment was equal in the 2 groups, and general well-being improved by 3.0 points more in the IC group (P=.05). Fear of self-injecting and self-testing did not differ. CONCLUSIONS: Bedtime NPH insulin added to maximal therapy with sulfonylurea and metformin is an effective, simple, well-tolerated approach for patients with uncontrolled type 2 diabetes.

Analysis of Variance↗
PubMed2004

[Effect of casein and protamine on the enzymatic degradation and the orally hypoglycemic action of insulin].

AIM: To study the protection of casein and protamine against degradation of insulin (INS) by proteolysis enzymes and the effect of these two kinds of protein on the hypoglycemic action of INS solution and enteric-microspheres after administrated orally to rats. METHODS: HPLC was used to determine the remained INS in the solution of alpha-chymotrypsin and trypsin with or without casein or protamine; INS solution and enteric-microspheres were prepared and adiministrated orally to rats together with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). At the same time, casein or protamine or both of these two kinds of protein were administrated together in order to study their influence on the hypoglycemic effect of INS and microspheres. RESULTS: Casein had a good protection against degradation of INS by alpha-chymotrypsin, but protamine had no protection effect. However, the degradation of INS by trypsin is concerned, the protection effect of protamine on INS was better that of casein. Both of protamine and casein can increase the hypoglycemic effect of INS solution and enteric-microspheres. Co-administrated these two kinds of protein had a better effect. In addition, co-administrated with SNAC, casein and protamine, INS enteric-microspheres had a longer and more potent hypoglycemic effect than that of the solution. CONCLUSION: Casein and protamine can increase the stability of INS in the intestinal fluid by the mechanism of competition and combine with proteolysis enzymes, which will benefit to INS oral administration.

Administration, Oral↗
PubMed2006

Comparison of lipid profiles and lipoprotein a levels in patients with type 2 diabetes mellitus during oral hypoglycemic or insulin therapy.

OBJECTIVE: The aim of this study is to compare lipid and lipoprotein (a) profiles in patients with type 2 diabetes mellitus (DM) on insulin and oral hypoglycemic therapy. METHODS: The study took place in the Department of Physiology, Army Medical College, Rawalpindi, Pakistan, during 2002. Ninety-seven type 2 DM patients participated in the study. We divided the patients according to the type of treatment into sulphonylurea (n=40), sulphonylurea plus metformin (n=33) and insulin (n=24) therapy groups as well as 40 healthy subjects served as controls. Fasting blood samples were analyzed for lipoprotein (a) [Lp (a)], total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, glycosylated hemoglobin (HbA1c) and insulin. RESULTS: Different groups of diabetic patients showed elevated fasting blood glucose (FPG) levels (p<0.0001 for all), HbA1c (p<0.0001 for all) compared with controls. Meanwhile, fasting insulin levels were elevated only in insulin treated group compared with oral hypoglycemic treated groups and controls (p<0.0001 for all). Patients on sulphonylurea and on sulphonylurea plus metformin groups showed significantly elevated TC (p<0.001, p<0.0001), TG (p<0.001, p<0.01), LDL-C (p<0.01, p<0.001) and LDL-C/HDL-C (p<0.0001, p<0.0001) compared with controls. Insulin therapy group showed significantly decreased TC, TG, LDL-C, LDL-C/HDL-C levels compared with sulphonylurea and sulphonylurea plus metformin treated groups, however, no significant difference was noted in the levels of above mentioned parameters and controls. Meanwhile, HDL-C levels were significantly lower in all diabetic groups compared with controls and were higher in insulin treated group compared with sulphonylurea plus metformin therapy group (p<0.05). Lipoprotein (a) levels were significantly higher in different diabetic groups compared with controls. While there was a non-significant difference in Lp (a) levels between different diabetic groups. CONCLUSION: Patients with type 2 DM who are being treated on insulin have a better lipid profile (TC, HDL-C, LDL-C, TG) compared with those patients on oral hypoglycemic agents. Meanwhile, Lp (a) levels were raised in all diabetic patients and seem not to be affected either by insulin or by oral hypoglycemic treatment.

Adult↗
PubMed2006

Clinical investigation of hypoglycemic effect of seeds of Azadirachta-inidca in type-2 (NIDDM) diabetes mellitus.

The present study was designed to investigate clinically the hypoglycemic effect of seeds of Azadirachta indica in Type-2 diabetes mellitus. After assaying fasting plasma and urinary glucose, 10 patients of type-2 diabetes mellitus with no previous medication, 10 patients of type-2 diabetes mellitus taking oral hypoglycemic agents with history of inadequate control and six control subjects were given low (0.5 g tid) and high (2 g tid) doses of powdered part, aqueous extract and alcoholic extract of Azadirachta indica for 14 days. On 15th day blood and urine samples for glucose were taken. Based on results obtained it was found that Azadirachta indica has significant hypoglycemic activity in high dose and can be successfully combined with oral hypoglycemic agents in type-2 diabetic patients whose diabetes is not controlled by these agents.

Azadirachta↗
PubMed1985

The role of oral hypoglycemic agents in therapy and prevention of macrovascular complications.

Of all the possible atherosclerotic factors, it must be accepted that only a few can be reached by today's diabetes therapy. Control of diabetes (hopeful, but not proven); Aging--useful but only in as much as good treatment might retard the aging process (questionable); Obesity--a great generality (possibly helpful); Lipids and lipoproteins (probably helpful, although more specifics needed); Hyperinsulinism (questionable--more studies underway); Platelet changes and coagulation (probably an important area--much investigation underway); There is no real evidence that any oral hypoglycemic agent is specific for treatment in these areas. Claims are made for some of the present oral hypoglycemic agents. Are these alleged benefits due to the specific properties of these agents or are they simply reinforcement of good diabetes control? There have been some specifically favorable reports of experiments with glicazide. If these are true, this would add another important dimension to its accepted hypoglycemic role. At this time, the oral hypoglycemic agents must be considered adjuncts in good control of diabetes and as such might provide a beneficial influence on atherosclerosis and macrovascular complications, but this is hardly specific.

Aging↗
PubMed1980

Ionophoretic activity of hypoglycemic sulfonylureas.

Hypoglycemic sulfonylureas, such as tolbutamide, gliclazide and glipizide, provoked the translocation of Ca from an aqueous medium into or across an organic immiscible phase. The amount of Ca translocated into the organic phase was proportional to the square of the drug concentration, and appeared saturable at high Ca concentration. Non-hypoglycemic sulfonylureas and diazoxide had little or no effect upon Ca translocation. The ionophoretic capacity of the hypoglycemic sulfonylureas was antagonized by suloctidil. Tolbutamide and gliclazide also provoked Na translocation into the organic phase, the amount of Na translocated being proportional to the drug concentration. Gliclazide-mediated Ca translocation was inhibited in a dose-related fashion by increasing concentrations of Na+ or H+. It is proposed that the ionophoretic capacity of hypoglycemic sulfonylureas may participate in their insulinotropic action.

Calcium↗
PubMed1983

Drug interactions of gliclazide and other sulfonylureas in protein binding in vitro and in hypoglycemic effect in rats.

Possible drug interaction in clinical use of a hypoglycemic sulfonylurea, gliclazide, was examined by two measures: its binding to protein in vitro and its hypoglycemic effect in vitro in the presence of other therapeutic agents. Binding of radiolabeled sulfonylureas to human serum albumin at its physiological concentration was determined by ultrafiltration in the presence of other agents. The concentrations of all agents examined were at their therapeutic (i.e., clinically observable) levels in the blood. Protein binding of [3H]gliclazide and [14C]tolbutamide was modified by salicylic acid and phenylbutazone but not by tolmetin, warfarin and propranolol. Binding of [3H]glibenclamide was not influenced by these agents under conditions employed. Blood glucose lowering effect of sulfonylureas was studied in rats to which other agents were given. The hypoglycemic effect of gliclazide and chlorpropamide was enhanced by concomitant administration of acetylsalicylic acid and phenylbutazone but not by dicumarol and warfarin. The enhancement of hypoglycemic effect is likely to result from the interaction of protein binding between the drugs.

Animals↗
PubMed1994

Hypoglycemic effects of three plants from eastern Himalayan belt.

Rhizome of Costus speciosus, tuber of Nephrolepsis tuberosa, and bulb of Stephania hernandifolia, used by the local people and traditional healers in the Eastern Himalayan belt, were studied for their effects on serum glucose levels in nondiabetic and diabetic rat models at different prandial states. The results showed that in nondiabetic rat C speciosus and N tuberosa had no significant effect in the fasting or postprandial state when freeze-dried juices were fed simultaneously with glucose. However, when fed 30 min before the glucose load both C speciosus (p < 0.05) and N tuberosa (p < 0.003) showed hypoglycemic effect. To the contrary, S hernandifolia increased the serum glucose levels of nondiabetic rats in all the series of experiments (p < 0.05 or p < 0.01). In NIDDM model rats N tuberosa opposed the rise in serum glucose level when it was fed 30 min before the glucose load (p < 0.02), whereas S hernandifolia had a tendency to raise the serum glucose level. In IDDM model rats, none of these three freeze-dried juice showed any effect in the fasting state. However, C speciosus showed significant hypoglycemic effect (p < 0.002) when the juice was fed with simultaneous glucose load. In marked contrast to the findings with nondiabetic and NIDDM model rats S hernandifolia showed significant hypoglycemic effect (p < 0.05-0.006) in both the stages (fed simultaneously with, and 30 min before the glucose load) of prandial states of the IDDM model rats. The results indicated that these three plants have interesting possibilities as a source of oral hypoglycemic agents.

Animals↗
PubMed1997

[Hypoglycemic effects of peroxovanadate complexes on glucose transportor of diabetic rats].

OBJECTIVE: To demonstrate the hypoglycemic effects and translocation of glucose transport (Glut 1 and Glut 4) promoted by peroxovanadate and nicotinic acid complexes (POR) in streptozotozin-induced diabetic rats. METHODS: Peroxovanadate complexes nicotinic acid (POR) was prepared in laboratory. POR and vanadate were administered in drink water. The muscles from diabetic rats were subjected to sucrose density gradient centrifugation to prepare plasma membrane and microsome membrane. Antibodies to COOH-terminal of glucose transportor were used in Western Blot to evaluate the translocation. RESULTS: Peroxovanadate complexes of nicotinic acid (POR) showed marked hypoglycemic effects on STZ-induced diabetic rats. 1mg/kg oral pathway POR could significantly reduce the plasma glucose levels (from 18.95 +/- 2.61mmol/L to 6.36 +/- 2.23mmol/L, t = 12.233, P < 0.01) over four week's treatment, whereas, same dose of single sodium vanadate or nicotinic acid did not have hypoglycemic effects. The net vanadium intake was about 1/90 of single effectively vanadate treatment. When Western blot was used POR increased the translocation of Glut 4 and Glut 1 from intracellular site of plasma membrane. CONCLUSION: Peroxovanadate-nicotinic acid complexes (POR) are the novel vanadyl that markedly reduce plasma glucose in a lower dose comparing to vanadate in STZ-DM rats by oral administration. Translocation of glucose transportor may play a part in hypoglycemic mechanism.

Animals↗
PubMed1985

The temporal evolution of hypoglycemic brain damage. II. Light- and electron-microscopic findings in the hippocampal gyrus and subiculum of the rat.

Part I of this paper has documented the evolution of dark neurons into acidophilic neurons in the superficial laminae as well as the reversion of dark neurons to normal neurons in the deep laminae of the cerebral cortex in hypoglycemic brain damage. The present study describes the temporal evolution of hypoglycemic brain damage in the hippocampus. The evolution of dark neurons to acidophilic neurons was confirmed in this brain region. Four additional problems were addressed: Firstly, delayed neuronal death was looked for, and was found to occur in areas of CA1 undergoing mild damage. However, it was not preceded by a morphological free interval, had ultrastructural characteristics distinct from delayed neuronal death in ischemia, and hence should be considered a distinct phenomenon. Secondly, the gradient in the density of neuronal necrosis in the rat hippocampal pyramidal cell band was exploited to test the hypothesis that a more severe insult causes a more rapid evolution of neuronal changes. This was found to be the case, with a temporal spectrum in the timing of neuronal death: Necrosis occurred already after 2 h medially in the subiculum, and was delayed by up to several weeks laterally in CA1. Thirdly, the almost universal sparing of CA3 pyramidal neurons after 30 min hypoglycemic isoelectricity was exploited to address the question of whether reactive changes, which could with certainty be deemed reversible, occur in CA3. Mitochondrial injury was seen in these cells, and was found to be recoverable. No reactive changes of the type previously described following ischemic insults were observed. Fourthly, the astrocytic and vascular response of the tissue was studied. A sequence of astrocytic changes representing structural and probably metabolic activation of astrocytes was seen, consisting of morphological indices of increased turnover of cellular components. Capillaries demonstrated endothelial pits, vesicles, and prominent microvilli hours to days after recovery. The results demonstrate that, in the hippocampal gyrus as in other brain regions, hypoglycemic brain damage is distinct from ischemic brain damage and likely has a different pathogenesis.

Animals↗
PubMed1982

Different endocrinological properties, growth rate and sensitivity to chemotherapy of aplastic mammary carcinoma in normo- and hypoglycemic phase of tumor growth.

An aplastic mammary carcinoma (AMC) grew slower in hypoglycemic mice (caused by fasting or by daily insulin injections) and in hyperglycemic mice (caused by alloxan or streptozotocin, or by daily injections of glucose) than in normoglycemic mice. The tumor was able to adapt to the unfavourable conditions of the diabetes; cells, when transplanted from diabetic donors into diabetic recipients, secreted immunoreactive insulin (IRI) and immunoreactive glucagon (IRG), which are deficient in the diabetic hosts. In the terminal (hypoglycemic) phase of tumor growth, the concentrations of glucose, IRI and IRG decreased. The immunological reactivity of the host animals was reduced in the hypoglycemic terminal phase. The tumor cells taken from hosts in this phase behaved differently from the cells taken in the normoglycemic phase. The "hypoglycemic" cells grew more slowly in healthy mice; the intensity of their DNA synthesis was diminished, their response to antitumor therapy was weaker. Furthermore, it was necessary to transplant more of these cells to obtain tumors in all recipients, and they lost their ability to adapt to diabetic conditions (i.e. secreted neither IRI nor IRG). Hypoglycemia was apparently the immediate cause of death in mice with AMC. Injections of glucose or glucagon into mice with AMC eliminated the hypoglycemia temporarily and postponed the death by 4 days. Mice treated with glucagon and with chemotherapy or immunotherapy survived 6-9 days longer than mice treated with chemo- or immunotherapy alone. Some of these differences between the end-stage and the progressively growing tumors could be explained in terms of tumor cell kinetics but some could be attributed to metabolic conditions of the host caused in part by the tumor.

Animals↗
PubMed1996

Hypoglycemic effect of copper(II) acetate imidazole complexes.

The effect of copper(II) complexes on glucose metabolism was studied in normal and streptozotocin-induced diabetic rats. The copper(II) complexes used were bis(acetato)tetrakis(imidazole) copper (II), [Cu(OAc)2(Im)4], bis(acetato)bis(2-methylimidazole) copper(II), [Cu(OAc)2(2mIm)2], bis(acetato)bis(1,2-dimethylimidazole) copper(II), [Cu(OAc)2(1,2dmIm)2], and bis(acetato)bis(mu-acetato)tetrakis(N-methylimidazole) copper(II) hexaaquo, [Cu2(OAc)4-(NmIm)4].6H2O. Intramuscular administration of various doses of Cu(OAc)2(Im)4 ranging from 10 to 100 mg/kg body mass to overnight fasted rats decreased blood glucose levels in a dose-dependent manner. Maximum hypoglycemic effect was observed 3 h after administration and lasted for at least 6 h. Treatment with 100 mg/kg body mass of Cu(OAc)2(Im)4 caused hypoglycemic shock, which was irreversible and even lethal. Blood insulin levels were reduced sharply during this hypoglycemic shock. Similar changes in blood glucose level were achieved using Cu(OAc)2(2mIm)2. The same pattern of hypoglycemia, although less pronounced, was observed for Cu2(OAc)4(NmIm)4.6H2O and Cu(OAc)2(1,2dmIm)2. Binary copper(II) acetate complex, the ligand imidazole, and the inorganic form of copper, such as copper(II) chloride, had no significant effect on blood glucose level. These results indicate that the hypoglycemic activity of these complexes varies with the imidazole ligand and structure of the complex.

Animals↗
PubMed1988

TPA (12-O-tetradecanoylphorbol-13-acetate) enhances the central hypoglycemic action of thyrotropin-releasing hormone in mice.

This study examined the effect of the calcium- and phospholipid-dependent protein kinase C (PKC) activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the plasma glucose responses to central thyrotropin-releasing hormone (TRH) injection in mice in order to evaluate the involvement of PKC in the mechanism of TRH action in the central nervous system (CNS). TRH (0.1-10 micrograms), as well as the neuroactive TRH analogs, CG 3509, CG 3703, DN 1417, RX 77368, [Nva2]-TRH, KPC-TRH, and TRH-Gly (0.1-10 micrograms), injected centrally in normoglycemic mice reduced the circulating glucose levels in a dose-dependent manner. TPA (0.1-1 microgram), administered centrally together with TRH (1 microgram) or the TRH analogs strongly enhanced the hypoglycemic response. Similar doses of TPA had no effect on plasma glucose when administered alone or together with TRH analogs devoid of central hypoglycemic action, i.e. [Glu1]-TRH, [Phe2]-TRH, and [Gly3]-TRH (1 microgram). Central injection of a TPA analog lacking PKC-stimulating activity, 4-alpha-phorbol (0.1-1 microgram) had no effect on the hypoglycemic response to coadministered TRH. These results, demonstrating a specific effect of TPA in enhancing the hypoglycemic response to central TRH or its neuroactive, though not inactive, analogs are consistent with a possible role for PKC in the mechanism of TRH action in the CNS.

Animals↗
PubMed1988

Hypoglycemic neuropathy in experimental diabetes.

Morphological and electrophysiological observations were made over 4 weeks on 5 groups of 8-week-old male Sprague-Dawley rats. These were comprised of controls, untreated diabetics, and diabetic animals in which sustained hypoglycemia, moderate hypoglycemia, or normoglycemia was induced by continuous subcutaneous insulin infusion (CSII) therapy. Teased fiber studies showed a marked increase in the number of myelinated fibers undergoing axonal degeneration and regeneration in the tibial nerve of severe hypoglycemic and also in moderate hypoglycemic animals but not in controls, untreated diabetic and normoglycemic groups. There was also a significant correlation between episodes of hypoglycemia (less than or equal to 2.0 mmol/l) and the prevalence of axonal degeneration and regeneration in CSII-treated diabetics. Motor nerve conduction velocity was significantly reduced in the moderate and severe hypoglycemic groups and also in untreated diabetic animals when compared with controls. However, it was significantly improved in the normoglycemic group over the untreated diabetic and severe hypoglycemic groups. In conclusion, this study has demonstrated that severe or even mild hypoglycemia produced a detrimental effect on peripheral nerve structure and function in experimental diabetes. Therefore, it may be desirable to avoid even asymptomatic hypoglycemia in the management of diabetes.

Animals↗
PubMed2004

Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytochrome P450 mediated mechanism in aged rats.

We examined hepatic cytochrome P450 (CYP)-mediated interactions between Ginkgo biloba extract (GBE) and tolbutamide, an oral anti-diabetic agent, in aged and young rats. Tolbutamide was orally given to rats with or without GBE treatment, and time-dependent changes in blood glucose were monitored. The basal activity of six CYP subtypes in liver was lower in the aged rats than in the young rats, while the inductions of these enzymes by 5 day pretreatment of 0.1% GBE diet were more in the aged rats. Further, the pretreatment of GBE significantly attenuated the hypoglycemic action of tolbutamide in the aged rats, corresponding well to the enhanced activity of (S)-warfarin 7-hydroxylase, which is responsible for CYP2C9 subtype, a major isoform metabolizing tolbutamide. In contrast, the simultaneous administration of GBE with tolbutamide potentiated the hypoglycemic action of this drug. The in vitro experiments revealed that GBE competitively inhibited the metabolism of tolbutamide by (S)-warfarin 7-hydroxylase in the rat liver microsomes. In the young rats, the 5 day pretreatment with GBE significantly attenuated the hypoglycemic action of tolbutamide, but a simultaneous treatment had little influence on the tolbutamide effect. In conclusion, the present study has shown that the simultaneous and continuous intake of GBE significantly affects the hypoglycemic action of tolbutamide, possibly via a hepatic CYP enzyme-mediated mechanism, particularly in the aged rats. Therefore, it is anticipated that the intake of GBE as a dietary supplement with therapeutic drugs should be cautious, particularly in elderly people.

Analysis of Variance↗