Eur J Clin Pharmacol (1991) 40:383-386

003169709100094I
Eorop.a0Joor0a, of
@ Springer-Verlag 1991
Di f f e r e nt i a l e f f e c t s o f s o di um bi c a r bo na t e and a l umi ni um hy dr o x i de
on t he a bs o r pt i o n and act i vi t y o f gl i pi zi de
K. T. Kivistii and P. J. Neuvonen
Department of Pharmacology, University of Turku, Turku, Finland
Received: July 5, 1990/Accepted: October 4, 1990
Summary. The effects of sodi um bi carbonat e and alumi-
ni um hydroxi de on t he absorpt i on and activity of glipizide
have been st udi ed in heal t hy vol unt eers in two ran-
domi zed cross-over trials. Af t er an overni ght fast, 5 mg
glipizide was given ei t her with 150 ml wat er or wi t h wat er
cont ai ni ng 3.0 g sodi um bi carbonat e or 1.0 g al umi ni um
hydroxi de.
Sodi um bi carbonat e significantly i ncreased t he AUC
of pl asma glipizide f r om 0 to 0.5 h, 0 t o I h, and f r om 0 to
2 h (six-, four- and t wofol d, respectively). The t i me to
peak concent r at i on (tm~) fell f r om 2.5 h duri ng t he cont rol
phase to 1.0 h duri ng t he sodi um bi carbonat e phase. The
absorpt i on half-life (tma), lag t i me and mean resi dence
t i me (MRT) were also significantly decreased. No signifi-
cant change in peak pl asma concent r at i on (Cmax), t ot al
AUC or el i mi nat i on half-life (tl/2) was not ed. The de-
cr ement al pl asma glucose areas f r om 0 t o i h and 0 to 2 h
were significantly larger (80% and 50%, respectively)
t han duri ng t he cont rol phase. The maxi mal decrease in
glucose was 50% great er duri ng t he sodi um bi carbonat e
phase, and t he t i me t o reach it was r educed by 35 rain.
Al umi ni um hydr oxi de had no significant effects on t he
rat e or ext ent of absorpt i on of glipizide, and t he glucose
response also r emai ned unaffect ed.
It is concl uded t hat t he concomi t ant i ngest i on of so-
di um bi car bonat e and glipizide may result in accel erat ed
absorpt i on of glipizide and an i ncreased effect on glucose.
A common dose of al umi ni um hydroxi de did not appear
to affect t he absorpt i on of glipizide.
Key words: Glipizide, gast roi nt est i nal absorption, sodi um
bi carbonat e, al umi ni um hydroxi de, glucose, drug interac-
tion, heal t hy vol unt eers
Glipizide is absorbed compl et el y and rel at i vel y rapidly,
even t hough it is onl y sparingly soluble in t he acidic gastric
cont ent s [1]. However, absorpt i on of glipizide and ot her
sul phonyl ure as may b e unusual l y slow in some heal t hy sub-
jects, as well as in cert ai n di abet i c pat i ent s [2-4]. It is oft en
r ecommended t hat sul phonyl ureas be t aken 30 mi n before
meals to ensure t hei r rapi d absorpt i on [5]. For example,
food can del ay the absorpt i on of glipizide, and t aki ng glipi-
zide on an empt y st omach has been shown to result in bet t er
disposition of glucose in diabetic pat i ent s [6].
Ant aci ds affect t he absorpt i on of many drugs, and
clinically i mpor t ant i nt eract i ons have been described [7,
8]. The consequences of drug-ant aci d i nt eract i ons are
very dependent on t he ant aci d used, but r educed absorp-
t i on of t he affect ed drug is most oft en encount ered. Mag-
nesi um hydroxi de and sodi um bi carbonat e may increase
the rat e of absorpt i on of certain weakl y acidic drugs, e.g.
t ol fenami c and mef enami c acids [9], and napr oxen [10],
respectively. On t he ot her hand, al umi ni um hydroxi de,
alone or in combi nat i on wi t h ot her antacids, typically re-
duces or delays drug absorpt i on [10-12].
Recently, magnesi um hydroxi de was shown to ac-
cel erat e the absorpt i on and increase t he glucose-lower-
ing effect of glipizide (Kivist6 and Neuvonen, unpub-
lished observations). There do not appear to be ot her
publ i shed dat a about t he possible effects of di fferent
antacids on t he absorpt i on of sul phonyl ureas. It was con-
si dered i mpor t ant to det er mi ne whet her addi t i onal inter-
actions coul d occur bet ween t hese two wi del y used drug
groups.
In the present study, t he effects of sodi um bi carbonat e
and al umi ni um hydroxi de on t he gast roi nt est i nal absorp-
t i on and glucose response of glipizide have been st udi ed in
heal t hy volunteers.
Materials and methods
General design
The present investigation comprised two separate studies. Six
healthy volunteers participated in the first study and 7 in the second.
All volunteers were considered healthy on the basis of medical his-
tory, physical examination, and routine laboratory tests (renal and
hepatic function, fasting glucose, haemoglobin). The subjects were
thoroughly informed, both verbally and in writing, and informed
consent was obtained. The study protocol was accepted by the local
Ethics Committee.
A randomized cross-over design was employed, with two phases,
at least one week apart. The test drugs were ingested after an over-
384
night fast t oget her with 150 ml water or with 150 ml wat er cont ai ni ng
the ant aci d studied. The subjects were kept supine, under direct
medical supervision, for 2 h from the begi nni ng of the study. No food
was allowed duri ng that time; breakfast was gi ven after t he 2 h bl ood
sample, and t hen the subjects were allowed to move and eat as
desired. Hypogl ycaemi c sympt oms were moni t or ed on t he study
days. Gl ucose bot h for oral and i nt ravenous admi ni st rat i on was
available i n case of severe hypoglycaemia. It was not needed.
Ti med venous bl ood samples from an i ndwel l i ng catheter were
collected i n hepari ni zed t ubes 0,15,22, 30 and 45 mi n, and 1,1.5, 2, 3,
4, 5, 7 and 10 h after drug ingestion. The t ubes were chilled on ice
bot h before and after sample collection. Pl asma was separat ed with-
in 30 rain at + 4 C, and t he samples were stored at - 20 C unt i l
analysed.
Effect of sodi um bicarbonate on glipizide absorption
One man and 5 women with a mean (SEM) age of 23 (0.8) y, and a
mean body weight of 59 (2.8) kg, i ngest ed 5 mg glipizide (Melizid,
Medica, Fi nl and) either with 150 ml water, or with 150 ml wat er con-
t ai ni ng 3.0 g sodi um bi car bonat e (NaHCO3; E. Mer ck, Darmst adt ,
West -Germany).
Effect o f al umi ni um hydroxide on glipizide absorption
Two men and 5 women with a mean (SEM) age of 23 (0.7) y, and a
mean body weight of 61 (3.7) kg, i ngest ed 5 mg glipizide (Melizid,
Medica, Fi nl and) ei t her with 150 ml water, or with 150 ml wat er con-
t ai ni ng 1.0 g al umi ni um hydroxide (AI(OH)3; E. Merck, Darmst adt ,
West -Germany).
Analytical methods
Pl asma glipizide concent rat i ons were det er mi ned by reversed phase
HPLC, using a modi fi ed versi on of two previously published met h-
ods [13, 14]. To i ml plasma, 0.5 M HC1 0.2 ml and 400 ng t ol but -
amide, t he i nt ernal st andard, were added. The sample was t hen ex-
tracted with 5 ml of a 1 : 1 mi xt ure of di chl oromet hane and hexane
and shaken for 4 mi n. Aft er centrifugation, t he organic phase was
evaporat ed to dryness under a st ream of ni t r ogen at 40 C. The
residue was redissolved i n 70 gl mobi l e phase, and a 20 ~tl aliquot was
injected i nt o t he chromat ograph. The mobi l e phase consisted of a
mi xt ure of met hanol and 0.01 M phosphat e buffer at pH 3.5 (55 : 45).
The flow-rate was 1.2 ml . mi n- t. The UV det ect or was set at 229 nm,
and t he sensitivity was kept at 0.02 a. u. f. s. The inter-assay coeffi-
cient of vari at i on was 4.4% ( mean 218 ng- ml t, n = 8).
K. T. Kivist6 and E J. Neuvonen: Absor pt i on and effect of glipizide
Pl asma glucose concent rat i ons up to the breakfast time (2 h)
were det er mi ned by the glucose oxidase met hod (Reflotron,
Boehri nger Mannhei m GmbH, West -Germany). The inter-assay
coefficient of vari at i on was 3.3% ( mean 5.6 mmol . 1 1, n = 8).
Pharmacokinetic analysis
The pl asma concent rat i on-t i me dat a for glipizide were fitted to an
open one- or t wo-compart ment model, whichever gave the bet t er fit,
by weighted least squares analysis, usi ng t he SI PHAR pharmaco-
ki net i c curve fitting programme (SIMED, Creteil, France). The ab-
sorpt i on of glipizide was characterized by t he peak t i me ( t m a x ) , half-
life of absorpt i on (tl/2a), lag time, peak pl asma concent rat i on ( C m a x ) ,
and t he areas under the pl asma drug concent rat i on-t i me curve from
0 to 0.5 h [ AUC (0-0.5 h)], 0 to 1 h [ AUC (0-1 h)], 0 to 2 h [ AUC (0-
2 h)], 0 to 10 h [ AUC (0-10 h)], and from 0 to i nfi ni t y ( AUC) . I n ad-
dition, estimates of mean residence t i me (MRT) and t ermi nal plas-
ma half-life (tin) were obt ai ned.
Glucose response
Gl ucose response was characterized by det ermi ni ng t he decremen-
tal areas under t he pl asma concent rat i on-t i me curve from 0 to 0.5 h,
0 to 1 h, and from 0 to 2 h. In addition, t he maxi mal decrease i n con-
cent rat i on, t oget her with the t i me to the maxi mal response, were
det ermi ned.
Statistical methods
Statistical analyses were made with the SYSTAT software package
(SYSTAT Inc., Evanst on, IL, USA) . Glipizide concent rat i on values
were analysed by analysis of vari ance for repeat ed measurement s.
Student' s t-test (two-tailed) for pai red values was used to det ermi ne
possible differences bet ween t he st udy phases. P < 0.05 was con-
sidered to be statistically significant. Results are expressed as means
(SEM).
Re s u l l s
Glipizide absorption
S o d i u m b i c a r b o n a t e a c c e l e r a t e d gl i pi z i de a b s o r p t i o n , as
r e f l e c t e d i n s i g n i f i c a n t c h a n g e s i n t i me t o p e a k , f r a c t i o n a l
e a r l y AUC v a l u e s , l a g t i me a n d a b s o r p t i o n ha l f - l i f e ( Fi g. 1;
7 0 0
6 0 0
500
@ 400 *
'5_ 500
2 0 0
h'- 1 0 0
0
0 1 2 3 4 5 7 10
T i m e ( h )
Fi g. L Effect of sodi um bi car bonat e (3.0 g, ~---o) on the absorpt i on
of glipizide (5 mg) shown as pl asma glipizide concent rat i ons. Mean
(SEM) of 6 subjects. *P < 0.05 compared to cont rol ( o- - o)
500-
E 400-
0"~
300 -
- o
f3_
o~ 2 0 0
o
o~
1 0 0 -
v
1 3 . .
0 t I I I I I I
0 1 2 3 4 5 7 10
T i me ( h )
Fig.2. Effect of al umi ni um hydroxi de (1.0 g, H ) on the absorp-
t i on of glipizide (5 rag) shown as pl asma glipizide concent rat i ons.
Mean (SEM) of 7 subjects. (O---O) control
K. T. Kivist/3 and E J. Neuvonen: Absorption and effect of glipizide 385
Table 1. Effect of sodium bicarbonate 3.0 g and aluminium hydroxide 1.0 g on the pharmacokinetics of glipizide 5 mg. Mean (SEM) of 6 and
7 subjects, respectively
Control NaHCO3 Control AI(OH)3
Peak time (h) 2.5 (0.22) 1.0 (0.21)"
Absorption half-life (h) 1.2 (0.25) 0.27 (0.09) a
Lag time (h) 0.28 (0.03) 0.22 (0.01) b
Peak concentration (ng/ml) 497 (75.2) 613 (68.8)
AUC ((~0.5) (ng-h-ml t) 12.2 (6.1) 78.5 (24.4) b
AUC (0-1) (ng-h-ml <) 73.1 (20.7) 316 (42.7) a
AUC (~2) (ng-h. ml z) 346 (111) 837 (87.5) ~
AUC (0-10) (ng-h-ml-1) 2330 (393) 2490 (443)
AUC (ng- h. ml <) 3540 (922) 3240 (841)
Elimination half-life (h) 4.8 (1.4) 4.2 (1.6)
Mean residence time (h) 8.3 (2.0) 6.1 ( 1 . 7 ) a
2.3 (0.18) 2.4 (0.32)
0.94 (0.18) 1.3 (0.28)
0.30 (0.03) 0.31 (0.06)
508 (58.4) 451 (21.3)
10.6 (5.4) 18.6 (8.9)
69.6 (17.6) 88.5 (32.9)
387 (82.9) 341 (81.7)
2230 (347) 2041 (268)
3250 (832) 2730 (629)
4.2 (1.3) 3.2 (0.66)
7.3 (1.8) 6.4 (1.1)
P < 0.01, b p < 0.05 compared to control
Table 2. Effect of sodium bicarbonate 3.0 g
and aluminium hydroxide 1.0 g on the glu-
cose response to glipizide 5 mg. Mean
(SEM) of 6 and 7 subjects, respectively
Control Na HCO3 Control AI ( OH) 3
Decremental area 0~3.5 h 2.05 (0.64) 2.72 (0.84) 1.76 (0.62) 2.31 (0.67)
(mmol-min.l-1)
Decremental area 0-1 h 25.5 (8.1) 45.5 (5.3) b 24.2 (6.8) 24.2 (8.6)
(mmol. min.l-2)
Decremental area 0-2 h 95.0 (19.9) 141 (14.7) b 110 (14.9) 96.6 (21.2)
(mmol-min-1 l)
Maximal decrease (mmol.I t) 1.52 (0.33) 2.23 (0.16) 1.81 (0.28) 1.70 (0.35)
Time of maximal decrease (h) 1.50 (0.18) 0.92 (0.05) a 1.50 (0.15) 1.36 (0.18)
a p < 0.01, b p < 0.05, c p = 0.06 compared to control
Tabl e 1). The AUC (0-0. 5 h), AUC (0-1 h) and AUC
(0-2 h) val ues wer e i ncr eased 6.4-, 4.3- and 2.4-fold, respec-
tively. The t i me t o peak concent r at i on was r educed f r om
2.5 h t o 1.0 h by sodi um bi car bonat e ( P < 0.01). The peak
pl asma concent r at i on, t ot al bi oavai l abi l i t y ( AUC) , and
el i mi nat i on half-life r emai ned essent i al l y unchanged, but
t he me a n r esi dence t i me was slightly r educed ( P < 0.01).
Al umi ni um hydr oxi de had no significant effect on any
of t he phar macoki net i c par amet er s refl ect i ng t he r at e or
ext ent of glipizide absor pt i on (Fig. 2; Tabl e 1). Never t he-
less, me a n pl asma glipizide concent r at i ons wer e hi gher for
up t o 45 mi nut es duri ng t he al umi ni um hydr oxi de phase,
whi l e t he AUC was 16% lower. Anal ysi s of var i ance f or
r epeat ed meas ur ement s i ndi cat ed a significant ( P < 0.001)
trials i nt er act i on in t he sodi um bi car bonat e st udy but not
in t he al umi ni um hydr oxi de study.
Glucose response
The decr ement al pl asma gl ucose areas f r om 0 t o i h and 0
to 2 h wer e 80% ( P < 0.05) and 50% ( P < 0.05) larger, re-
spectively, duri ng t he sodi um bi car bonat e phase t han dur-
ing t he cont r ol phase (Fig.3; Tabl e 2). In addi t i on, t he
maxi mal decr ease in glucose was 50% gr eat er ( P = 0.06)
and t he t i me t o this r esponse 35 mi n shor t er ( P < 0.01).
The gl ucose r esponse was not af f ect ed by al umi ni um
hydr oxi de (Fig. 3; Tabl e 2).
Other findings
Most subjects exper i enced mild t o moder at e hypo-
gl ycaemi c sympt oms, e. g. pal pi t at i on, sweating, and
t r emor of t he hands on bot h st udy days, whi ch peaked at
1-1.5 h. However , t he sympt oms always subsi ded spon-
t aneousl y, and t he subjects suf f er ed no distress af t er t he
2 h bl ood sample. It was not necessar y to admi ni st er
gl ucose f or t he sympt oms.
Di scussi on
Sodi um bi car bonat e significantly accel er at ed t he absorp-
t i on of glipizide in t he pr esent study, whi l e al umi ni um hy-
dr oxi de showed no effect. The t ot al ext ent of absorpt i on,
however, was not af f ect ed by ei t her antacid. Recent l y,
magnesi um hydr oxi de was f ound significantly t o i ncrease
t he earl y bi oavai l abi l i t y of glipizide, resul t i ng in enhanced
insulin and gl ucose responses (Kivist6 and Neuvonen, un-
publ i shed observat i ons).
The preci se mechani sm( s) causing t he obser ved glipi-
zi de- ant aci d i nt er act i on is not clear. Gl i pi zi de is a weakl y
acidic drug, whi ch is non- i oni zed but sparingly sol ubl e in
wat er at gastric pH. Di ssol ut i on is of t en t he rat e-l i mi t i ng
step in drug absorpt i on, and t he findings mi ght suggest
t hat t he absor pt i on of glipizide was accel er at ed by magne-
sium hydr oxi de and sodi um bi car bonat e, because t hey in-
cr eased its solubility by el evat i ng t he gastric pH. It is of in-
t er est t hat 1.0 g al umi ni um hydr oxi de had no effect on t he
phar macoki net i cs of glipizide. However , in vi t ro findings
i ndi cat e t hat magnesi um hydr oxi de at doses similar t o
t hose her e el evat es t he gastric p H t o a much hi gher l evel
t han al umi ni um hydr oxi de [15]. Mor eover , al t er ed gastric
pH is onl y one possi bl e mechani sm cont r i but i ng to t he in-
t eract i on. Magnesi um ions and el evat ed gastric pH may
i ncrease t he gastric empt yi ng rat e, enabl i ng drugs t o r each
t he small i nt est i ne mor e quickly. On t he ot her hand,
al umi ni um ions can del ay gastric empt yi ng and so de-
386
E
E
if)
0
o
13
E -
m
h-
6
5
4
3 I
2.
0
I I I I I I
15 30 45 60 90 120
Time { mi n)
E
E
03
o3
0
(J
2 3-
oa
o
E
2
0
(3_
4 "
0
I I I I I
15 30 45 60 90 120
Time (rai n)
Fig. 3. Plasma glucose concentrations after intake of 5 mg glipizide
with sodium bicarbonate (3.0 g, c --) or aluminium hydroxide
(1.0 g, A A). Mean (SEM) of 6 and 7 subjects, respectively. *signifi-
cant (P < 0.05) difference in concentration change between antacid
and control (o--o) phases
cr ease t he r at e of abs or pt i on of ma ny drugs. Thi s effect ,
t oget her wi t h t he adsor pt i ve pr oper t i es of al umi ni um
compounds , ma y count er act t he effect s of el evat ed gast ri c
p H on t he abs or pt i on of glipizide.
The dose of s odi um bi car bonat e (3.0 g) used her e was
r el at i vel y high. On t he ot her hand, ma n y over - t he- count er
pr epar at i ons cont ai n consi der abl e quant i t i es of s odi um
bi car bonat e, and t hey ma y be t aken in excessi ve doses for
mi nor gast r oi nt est i nal upset s.
The concomi t ant i ngest i on of glipizide and s odi um bi-
car bonat e r esul t ed in i ncr eased decr ement al gl ucose ar ea
and a gr eat er maxi mal gl ucose r esponse. The r el at i onshi p
be t we e n t he bl ood l evel of a sul phonyl ur ea drug, insulin
secret i on, and r educt i on in bl ood gl ucose is compl ex [16].
I n an ear l i er study, t he enhanced gl ucose r esponse t o glipi-
zi de pr oduced by ma gne s i um hydr oxi de was associ at ed
wi t h i ncr eased pl as ma insulin levels, due t o accel er at ed
abs or pt i on of gl i pi zi de (Ki vi st 6 and Neuvonen, unpub-
l i shed obser vat i ons) . The effect of s odi um bi car bonat e
can pr oba bl y be ascr i bed t o t he s ame mechani s m.
Advi ce is of t en gi ven t o t ake sul phonyl ur eas 0.5 h be-
f or e meal s in or der t o pr oduce an effect i ve dr ug l evel by t he
t i me of t he gr eat est met abol i c i mpact of t he meal [5]. I n a re-
cent study, del ayed gl i pi zi de abs or pt i on was not ed bot h in
cer t ai n heal t hy subj ect s and in s ome di abet i cs [2]. A1-
K. T. Kivist6 and R J. Neuvonen: Absorption and effect of glipizide
t hough age and di abet es a ppe a r t o have little effect on t he
phar macoki net i cs of glipizide [2], aut onomi c neur opat hy,
resul t i ng in del ayed gast ri c empt yi ng, ma y be an addi t i onal
cause of var i abl e abs or pt i on in di abet i c pat i ent s [4]. Shoul d
slow or er r at i c abs or pt i on of gl i pi zi de be a clinical pr obl em,
t he concomi t ant i nt ake of ma gne s i um hydr oxi de or sodi um
bi car bonat e mi ght be wor t h t ryi ng in or der t o enhance t he
abs or pt i on and ef f ect of glipizide.
To summar i ze, sodi um bi car bonat e accel er at ed t he ab-
sor pt i on and enhanced t he ef f ect of glipizide. Thi s i nt er ac-
tion, whi ch was not s har ed by al umi ni um hydr oxi de, has
pot ent i al clinical si gni fi cance as t he t her apeut i c r ange of
hypogl ycaemi c drugs is r el at i vel y narrow.
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283
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Schepper PJ (1979) Effect of aluminium hydroxide on diflunisal
absorption. Br J Clin Pharmacol 7:519-522
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chromatographic determination of glipizide and some other sul-
fonylurea drugs in serum. J Chromatogr 164:541-546
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determination of glipizide in human plasma and urine. J Chro-
matogr 421:31%326
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antacid suspensions marketed in Finland. Acta Pharm Fenn 91:
153-173
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Clin Pharmacokinet 16:100-128
Dr. K. T. Kivist6
Department of Pharmacology
University of Turku
Kiinamyllynkatu 10
SF-20520 Turku, Finland