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DIABET 00563
Summary
Key words: Kinetics; Metabolism; First phase insulin response; Sulphonylurea; Diabetic complication; Insulin
receptors; Haemobiology
Distribution
Biological assay Gliclazide, like most other sulphonylureas, is highly
bound to albumin in plasma (95% range 85-99%)
The most sensitive, specific assays for gliclazide use [5]; a few drugs can displace gliclazide in vitro [ 151,
high performance liquid chromatography [6-81. A but no such clinically significant interactions have
TABLE I
Pharmacokinetics of gliclazide after a single oral dose to healthy human volunteers
Mahajan et al., 1984 [I 171 3F-6M 22+ 1 80 4+1 3.9+ 1.9 10.2+ 3.8 26f7 32+13
Hopkins et al.. 3F-5M 34+13 80 6+2 5.0+ 1.4 8.0+ 1.8 13+4 18+ 4
1975 [I 141
Kobayashi et al.. 1984 [24] 12Mb 36-t 5 40 3-+1 5.61 1.8~ 12.3 + 3.9 17t7 16+ 6
Forette et al.. 1982 [22] 4F 26+ 4 80 4fl 6.3 + 2.6 11.8+0.7 13t5 13+ 6
Oida et al.. 1985 [19] 5Mb 37i 1 40 4d 5.2 * 0.4c 8.1+ 1.1 12d 17d
dApparent oral values assuming complete absorption (F=l); bJapanese subjects - all others are European; ccorrected for an 80
mg dose assuming linearity; dindividual value to calculate standard deviation not given
S23
TABLE 2
Reference Patient Dose Age No. T,,, CP,,, t/: Vd/F* CL/Fd
(Freqjmg) (Y) (h) (h) (L) (ml mini)
Kobayashi et al.. Diabetic S/80 48+10 12 3.0 -t 2.0 4.5k2.2 11.6f5.2 18+8 18+2
1984 [24] (193 mg 100 ml-)a
Campbell, Diabetic/renal s/40 46+16 6 4.0-t 1.0 3.1 kO.8 14.8 * 8.4 29f 18 26f 17
1985 [I 151 (44 +4l ml min-r)c
Campbell, Renal s/40 40+20 II 5.05 1.0 3.1 * 1.0 22.4 t 5.0 30*14 21+ 9
1985 [115] (13*9 ml min-r)C
Forette et al., Elderly S/80 77*4 5 6.0f 1.0 4.0 + 6.0 20.5f4.0 24+ 7 l4+ 3
1982 [22] (7 l-82)b
Kobayashi et al., Diabetic R/80 - 4 3.0t 1.2 7.6 f 2.4 12.3 + 2.6 16& 6~ 14+ 4~
1981 [29] (193 mg 100 ml-r)r
S = single dose; R = repeat dose for 7 days: - = not given; + = standard deviation,
Fasting blood glucose; bage range; Ccreatinine clearance; dapparent oral values assuming complete absorption (F = 1): cafter repeated
dosing - taken from AUC over one dosing interval (O-24 h).
S24
unchanged at around 15 ml min-1, leading to com- a dose dependent effect of gliclazide on platelets,
parable steady state levels in young (3.3 (*g ml-l) independent of hypoglycaemic activity.
and in elderly subjects (4.5 pug ml-i) [23]. Similarly,
there are no significant differences in the diabetic
subject [24]. In renal disease with or without
diabetes, the volume of distribution and half-life
(approximately 20 h) are increased [25], but the
small change in plasma gliclazide clearance is
unrelated to creatinine clearance [5] and no dosage
changes are necessary. No studies have been un-
dertaken in patients with hepatic disease, but it
can be anticipated that the dosage should be
reduced, as gliclazide is extensively metabolised. I
3 6 9
Blood glucose CCxICentmtlOns (mmol/l )
Kinetic-dynamic relationships
Single dosing 40
(b)
t
Gliclazide causes a dose-dependent fall in blood
zd I
glucose concentration in both volunteers and type
5 30
2 diabetic patients, but peak insulin responses
precede peak drug levels [26], and the two are not i_ \
Efficacy persists for some years [34,35] and the omised dogs and alloxan diabetic rats [48]. The
incidence of side effects, especially hypoglycaemia insulinotropic action has been confirmed in vivo
[30,36] is low. There is relatively little weight gain, with animal models of type 2 diabetes [49] and
and patients who are dieting can continue to lose in vitro with pancreatic tissue, isolated islets [50]
weight [23,34,37-401. and isolated perfused rat pancreas [51]. There is
Gliclazide ameliorates the defect in first phase a dose-related stimulation of insulin from pancre-
insulin response to intravenous glucose in type 2 atic tissue over therapeutic concentrations of gli-
patients [41,42]. There is a smaller effect on tardive clazide (0.2-20 pg ml-t) in the presence of glucose,
phase secretion, and this may explain a relatively which is characterised by a rapid early peak of
lower incidence of hypoglycaemia and lack of insulin, followed by a slower and sustained secon-
weight gain with gliclazide. dary phase [52]. Sulphonylureas stimulate insulin
release through a specific sulphonylurea receptor
P-cell pancreatic activity on the plasma membrane of the /?-cell which is
closely linked to an adenosine triphosphate sen-
Like all sulphonylureas, gliclazide causes a rapid sitive potassium channel (K+,r,). Although com-
rise in immunoreactive insulin and prolonged de- pounds vary widely in the binding affinities to this
crease in glycaemia following intravenous injection receptor, there is a reasonable correlation between
in dogs [47]. The effect is abolished in pancreatect- binding and clinical dosage [53], Rb+ efflux from
TABLE 3
Glucose clearance
Ward et al., 1985 [44] D 6 SO-160 3 +33 300 mU kg-1 h-1
Bak et al., 1989 [45] D 9 160-320 2 +50 75 @U ml-1
Johnston et al., 1988 [63] D 20 160 2 +46 100 @U kg- h-t
Ma et al., 1989 [65] D 9 160 4 +31 120 mU rn? min 4.5 mU h-1
Wajchenberg et al., 1987 [43]
FBGd> 200 mg dl-t D 80-160 3 +90 6 PU ml-1
FBGd< 200 mg ml-1 D 80-160 3 +51 6 /IU ml-r
Marchand et al., 1983 [I 161 D 160 2 NC
Lisato et al., 1988 [46] D 240 SDc NC 10 @LJml-1
Insulin binding
Ward et al., 1985 [44] OD 80-160 3 NC RBC, monocytes
Bak et al., 1989 [45] D 160-320 2 NC Solskeletal muscle
Wa.jchenberg et al., 1987 1431 D 80-160 3 NC/-30~ RBC
Marchand et al., 1983 [I 161 D 160 2 NC RBC
-
aD =diabetic; OD =obese diabetic; binsulin levels or infusion rate and human cells (insulin binding): SD = single oral dose;
dFBG = fasting blood glucose; eB,,, affinity only; NC = nonsignificant change, all other values are significant.
S26
(b) Gliclazide
Fig. 2. The action of (a) glucose and (b) gliclazide on insulin secretion from the fl-cell. (a) Glucose is (1) transported into the
cell (2) increasing the ATP/ADP ratio which (3) inhibits the K+ ATP channel by binding to the cytoplastnic side of the membrane.
This depolarises (4) the cell which (5) opens the voltage-dependent channel allowing (6) an increase in cytosolic calcium to (7)
activate insulin release. In addition, (8) glucose may have a direct effect on Ca *+ channels by increasing c-AMP. Finally (g) the
intracellular Cal+ activates the CaJ+ dependent KT channel to repolarise the cell. (b) Gliclazide (1) binds the sulphonylurea receptor
through a lipid matrix and (2) inhibits the K+ ATP channel which (3) depolarises the cell and (4) stimulates intracellular Calf
transport which is (5) translocated within the cell before (6) stimulating insulin microtubules (7). Gliclazide may also have a direct
effect on Ca?+ transport distal to locus of action of channel blockers.
insulinomas [54], and other measures of effect the glucose stimulated cyclic AMP mediated insulin
suggesting that the receptor is at least indirectly release [50].
functional. K+Arr channels have now been found in many
The binding of gliclazide and other sulphonyl- cells of the body, including cardiac muscle [58],
ureas to the receptor on the extracellular surface and they may play a physiological role in protecting
of the P-cell inhibits the efflux of Kf from the cell the cell against ischaemia and cell death by indi-
(Fig. 2). Subsequent depolarization of the cell and rectly stabilising intracellular K+ and calcium levels
change in the membrane potential activates the [59]. This may explain the protective activity of
opening of membrane voltage-dependent calcium gliclazide on cardiac arrhythmias experimentally
channels, allowing extracellular calcium to enter induced in dogs by coronary artery occlusion, since
the P-cell. This increase in free intracellular calcium they would inhibit the loss of K+ from ischaemic
ion acts as a second messenger to induce phos- cardiac muscle [60]. Recently it has been shown
phorylation of proteins which in turn stimulate that gliclazide may also exert an effect on potassium
extracellular insulin release. There is also evidence transport by indirectly inhibiting the Na+, K+-
to suggest that gliclazide may have a primary direct ATPase pump transport mechanism [61]. The im-
action on increasing Caz+ inflow into islet cells, portance of this finding has yet to be determined
in addition to its indirect action through sulpho- [6]. The initial elevation of insulin levels disappears
nylurea K+*rr binding site [55,56]. In addition, it during long term sulphonylurea treatment, but
alters the distribution of calcium within the cells, blood glucose concentrations remain lower. In an
increasing the levels in the cytoplasmic matrix and attempt to explain this apparent paradox, it has
secretory granules [57]. Indeed, temporal differen- been suggested that sulphonylureas also improve
ces in the action of sulphonylureas on intracellular insulin action. This might result from an increase
calcium distribution may explain their different in receptor affinity or number, or improved post-
effects on 1st and 2nd phase insulin secretion. It receptor function, with enhanced glucose uptake,
has also been suggested that gliclazide may enhance storage and metabolism.
S27
Fig. 3. The haemobiological actions of gliclazide. Gliclazide reduces (1) platelet adhesiveness and the (2) release of platelet factors
(5HT. ADP, PG peroxides). reducing (3) platelet aggregation which would occur due to continual diabetic vascular damage and
interaction with underlying collagen. The reduction in release of platelet factors also reduces (4) vasoconstriction and vascular
permeability allowing (5) more 0, to be transported and reducing the anoxia and (6) reperfusion damage produced by oxygen
free radicals (02-) which are also reduced by gliclazide. The stimulation (7) of tissue plasminogen activator (t-PA) to increase
fibrinolysis also reduces vascular damage, (8) basement membrane thickening with a reduction in the necessity for repair enzyme
NABG and the potential for (9) long term atherosclerosis. (-) Reduces; (f) increases.
sclerotic plaques, retinopathy, nephropathy and platelets which are less active [83] and an overall
cardiovascular disease. reduction in platelet density [89]. Gliclazide halves
platelet hyperactivity, apparently by inhibiting the
synthesis and action of thromboxane A2 (TXAz)
Platelet adhesion and aggregation [82,91,92] and increasing the concentration of in-
traplatelet cyclic AMP (Fig. 4).
In both diabetic animals and man, gliclazide has Low cyclic AMP levels are found in hyperactive
been shown to reduce significantly the abnormal platelets and gliclazide has been shown to increase
platelet adhesiveness and subsequent aggregation the formation of intraplatelet cyclic AMP ex vivo
[33,77] (Fig. 3). Thus, intravenous or oral admin- in treated diabetic patients using [jH]adenosine or
istration at doses ranging from 5-100 mg kg-i adenine as precursors [93]. This activity is thought
gliclazide reduced Salzman glass bead retention and to occur by inhibiting glycolysis and maintaining
adhesiveness of platelets in rabbits [78,79] and dogs glycogen levels thereby stimulating adenylate cy-
[78] whilst tolbutamide did not [80]. Similarly, clase activity [93,94], since gliclazide has no inhib-
Duhault et al. [60] found that gliclazide pretreat- itory action on phosphodiesterase. The resulting
ment in dogs reduced the retinal capillary occlusion effect is a demonstrable reduction in the release
caused by carotid injection of ADP to aggregate of platelet factors, such as 5HT, P-glucuronidase,
platelets, whilst tolbutamide was inactive. In many ATP, ADP [95] and factors IV, V and VIII in
clinical studies reviewed by Holmes et al. [33] in animals and factor VIII in man [96], and an
more than 350 patients treated for up to 2 years, inhibiting effect on collagen-stimulated activation
there were significant reductions in platelet adhe- of platelet coagulation factor XI [83]. Despite these
sion with effects comparable to those achieved with effects on platelet function, no consistent changes
high dose aspirin or dipyridamole [8 11. Other more in coagulation or bleeding time have been reported
recent studies [34,82] have confirmed these earlier in the clinical studies where this has been examined.
findings with a reduction in adhesiveness of up to
25% maintained over a 3 year period. Gliclazide
has been shown to reduce platelet aggregation in Free radical activity
animals [79,83] whilst tolbutamide does not; similar
observations were made in diabetic [79] patients Free radicals, particularly the superoxide oxygen
in response to ADP [84-861, adrenaline [87] and free radical, are involved in the disruption of
collagen [85,88]. Similarly, treatment with glicla- cardiovascular homeostasis and are implicated in
zide for periods up to 9 months have reduced the oxygen reperfusion injury, atherosclerosis, EDRF
plasma PTG, an index of platelet hyperaggregation, turnover, and neutrophil phagocytosis. They could
by up to 60% [84,89] and intraplatelet /3TG by therefore contribute to diabetic macrovascular
45% [89]. There is some debate as to whether these disease, particularly since diabetic patients are
platelet effects are merely a consequence of lowering under greater oxidative stress [97], show greater
of blood glucose [31,89] or, as seems more likely, free radical activity [89] and have an impaired
an independent effect of gliclazide [32,87], since antioxidant defence mechanism [8]. Florkowski et
normalisation of blood glucose does reduce flTG al. [82] have shown that, following gliclazide treat-
[90] but apparently not to the same extent as ment, there is a reduction in the platelet aggregation
gliclazide. Other oral hypoglycaemic drugs have a markers of TXB2 and /3TG which coincided with
variable effect on platelet function [85,86,89]. Gli- a reduction in free radical activity as shown by
clazide is specifically taken up by the platelets a lowering of lipid peroxidases by 55% and oxi-
concentrating in the lysosome-like sub-cellular gra- dative proteins by 78%. Subsequently, Scott et al.
nules [88], with a reduction in heavy and meta- [99] found that gliclazide at therapeutic levels of
bolically active platelets and an increase in light 5 1.18 ml-i had a marked free radical scavenging
s30
(a) lb)
PHOSPHOLlPlDS THROMSOXANE A2
I
4
I
ARACHIDONIC ACID
PHOSPHOLIPASE A2 I-, GLICLAZIDE
BOUNDCa- __+
1 FREE&+ __, [m]
ENDOPEROXIDES
T SYNTHETASE/ \ P SYNTHETASE
THROMBOXANE A2 1
GLICLAZIDE ,+, ,-I D,PR,DAMlJLE
Fig. 4. The action of gliclazide on prostaglandin metabolism in the reduction of platelet adhesion and aggregation. Gliclazide is
thought to act at two sites within the platelet in the arachidonic activation of aggregation by: (a) inhibiting phospholipase Al
thereby reducing platelet thromboxane Al without affecting cell wall prostacyclin; (b) reducing thromboxane A: function by increasing
adenylcyclase activity thereby increasing platelet CAMP, whtch activates the protein kinase induced reduction in free Ca?+ to bound
Caz+ which opposes the thromboxane A2 stimulation of aggregation.
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s34
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