antiulcer prostaglandin misoprostol: single and multiple dose pharmacokinetic profile

PROSTAGLANDINS

ANTIULCER PROSTAGLANDIN MISOPROSTOL: SINGLE AND MULTIPLE DOSE PHARMACOKINETIC PROFILE

AZIZ KARIM

Searle Research and Development, Division of G. D. Searle & Co.,

4901 Searle Parkway, Skokie, IL 60077, U.S.A.

ABSTRACT

Low misoprostol dose (~g range), extremely low plasma levels (pg range) of misoprostol acid, and the necessity of using a complex, time consuming, and labor intensive RIA method of analysis make it technically difficult to study the pharmacokinetic profile of misoprostol in man.

The clinical relevance of the misoprostol pharmacokinetic data should be interpreted with care in view of the com- bined local and systemic effects of the drug.

The studies presented in the present review indicate:

Extensive metabolism of misoprostol occurs during and/or prior to gastrointestinal absorption.

Several metabolites are formed and no unchanged drug is detected in the plasma or urine.

The biologically active metabolite in the plasma is misoprostol acid (SC-30695), a de-esterified derivative of misoprostol.

Absorption of misoprostol and/or misoprostol acid is extremely rapid resulting in peak plasma levels of misoprostol acid in less than 15 minutes. Absorption probably occurs in the stomach.

The elimination half-life of misoprostol acid is short (less than 30 minutes).

No accumulation of misoprostol acid occurs in plasma following a 400 ~g ql2h dosing regimen of misoprostol.

INTRODUCTION

Prostaglandins are naturally-occurring substances with known effects on the gastrointestinal tract, including the inhibition of gastric acid secretion and the protec- tion of the mucosa against a variety of noxious stimuli.

40 SUPPLEMENT TO VOL. 33

PROSTAGLANDINS

Misoprostol [Cytotec®; SC-29333; (+)methyl(ll~,13E)- ll,16-dihydroxy-16-methyl-9-oxoprost-13-en-l-oate; Figure i], a synthetic prostaglandin E I analog, is an antiulcer drug which has demonstrated antisecretory and cytoprotective properties. This presentation reviews the single and multiple dose pharmacokinetic profile of misoprostol in healthy human subjects.

MISOPROSTOL: PHYSICOCHEMICAL PROPERTIES

Misoprostol has a molecular weight of 382.54, an empiri- cal formula of C22H3805, and exists as an approximate i:i mixture of two diastereomers. It is stabilized by a i:i00 dispersion on hydroxypropyl methylcellulose (HPMC). The basic pharmacology of the drug is not altered when misoprostol is administered as the HPMC dispersion.

DISTRIBUTION AND METABOLISM OF TRITIUM-LABELED MISOPROSTOL

The disposition and metabolism of misoprostol in man was studied with 17,18-tritium-labeled compound. Six healthy subjects (mean + SD age = 25.7 + 4.0 years; height = 175.3 + 9.2 cm? weight = 75.6 T 4.0 kg) received a single oral dose in water of--386 + 19.6 ~g of [17,18-3H]-misoprostol dispersed on HPMC. A--high performance liquid radiochromatogram of methanol extract- able tritiated materials in the plasma obtained 5 min after oral dose showed essentially no radioactivity associated with unchanged drug (Figure 2). One of the major metabolites in the plasma was the biologically active de-esterified compound, misoprostol acid (SC-30695). Others were the polar inactive dinor (III) and tetranor (IV) acid metabolites (Figures 1 and 2).

Mean plasma concentration-time curves of total 3H and misoprostol acid are illustrated in Figure 3. Mean ± SD peak plasma concentrations (Cmax) of 6.08 + 1.64 ng total 3H (misoprostol equivalents)/ml and 499 _+ 152 pg misoprostol acid/ml occurred at 30 + 0 min and 12 + 2.9 min, respectively. The decline of ~H in the plasma occurred with half-lives (tl/2) of 1.51 + 0.44 (fast phase) and 177 + 63.7 (slow phase) hrs. --The latter tl/2 was attributed to tritiated water produced from [17,18-3H]-misoprostol. The elimination tl/2 of the biologically active misoprostol acid was only 20.6 ~ 2.2 min.

Cumulative excretion of radioactivity in the urine and feces of the six subjects are illustrated in Figure 4. During a 7-day period, 73.2 + 11.3% of the administered radioactive dose was excreted in the urine. Most of

SUPPLEMENT TO VOL. 33 41

PROSTAGLANDINS

(+_)

O O

~o °1 6 CH 3 ~ CH 3 19

HO OH

I; SC-29333; Misoprostol

~ , ~ . " ~ C O O H (+) ~ I CH3

OH HO II; SC-30695; Misoprostol Acid

(+--) ( I CH3

Hd OH III; SC-41947; Dinor Acid Metabolite

o ) ) ~ . ~ C O O H

(+--) ( I CH3

IV; SC-41411; Tetranor Acid Metabolite

Fig. i. Structures of misoprostol (I), its biologically active misoprostol acid metabolite (II), and inactive dinor (III) and tetranor (IV) acid metabolites.


P R O S T A G L A N D I N S

6 0 0 -

5 0 0 -

4 0 0 -

3 0 0 -

Fig. 2.

Fig. 3.

O

I

. , , .a

200 L

o

100

0 5 I0 15 20 26 30 35 40 45 50 55

Time, r a in

A r e p r e s e n t a t i v e h igh pe r fo rmance l i q u i d r a d i o - chromatogram of the methanol eluent from Bond Elut TM extraction of the plasma sample collected 5 min after oral administration of [17,18-3H] - misoprostol to a human subject. The SC number corresponds to the identity of a synthetic standard with the respective elution time.

10000=

" ~ 1000

:, o

1oo o

1 ; 3~0 f 910 ~ i r i I o ~o 1 o t5o 18o z l o z4o T i m e , ra in

Mean plasma concentration-time curves of total radioactivity ( • ) and misoprostol acid metabolite (e) in six subjects following single 386 ~g oral doses of [17,18-3H]-misoprostol.

S U P P L E M E N T T O V O L . 33 43

P R O S T A G L A N D I N S

k , O > o o

O

>

1 0 0 -

90-

80-

70

6 0

5 0

4 0

3 0

I

v m m 1 I I I I I I

0 :24 48 72 96 120 144 168

Time, hrs

Urine

Z Z Z "r Z Urine

F e c e s

+ Feces

Fig. 4. Cumulative (mean + SE) excretion of radioactivity in urine and feces of six subjects following single dose administration of [17,18-3H] - misoprostol.

this excretion occurred in the first 24 hours. A typical high performance liquid radiochromatogram of tritiated materials present in the 0-i hr urine sample is illustrated in Figure 5. Total urinary excretion of unchanged misoprostol and its acid metabolite constituted less than 1% of the dose. Most of the urinary radioactivity was due to polar materials which included the dinor (III) and tetranor (IV) metabolites.

Excretion of radioactivity in the feces amounted to 14.7 + 7.7% of the dose and here excretion of 3H in the first--24 hrs was less than 5% of the dose. The fecal radioactivity was entirely due to the polar metabolites of misoprostol. The presence of radioactivity in the feces was attributed not to the unabsorbed drug but to the biliary excretion of misoprostol metabolites. From the excretion of the radioactivity in the urine and feces it was estimated that an average of at least 88% of the oral dose of [17,18-3H]-misoprostol was absorbed.

Since misoprostol acid was the major biologically active material in the plasma, a sensitive and specific radio- immunoassay (RIA) with a detection limit of 23 pg/ml of plasma was developed for this metabolite. This RIA method was utilized in the clinical pharmacokinetic and bioavailability studies described below.

44 S U P P L E M E N T TO VOL. 33

PROSTAGLANDINS

1600

1 4 0 0

1 2 0 0

0 0 I000 O

;~ 800

600 ,oo 200

1

5

~D o o c~

I w

I0 I15 2'0 2'5 30 35 40 415 510 515 Time, m i n

Fig. 5. A representative high performance liquid radiochromatogram of the methanol eluent from Bond Elut TM extraction of the urine sample collected at 0-i hr after oral administration of [17,18-3H]-misoprostol to a human subject. The SC number corresponds to the identity of a synthetic standard with the respective elution time.

RELATIONSHIP BETWEEN DOSE OF MISOPROSTOL AND PLASMA LEVELS OF MISOPROSTOL ACID

The relationship between the oral dose of misoprostol and plasma levels of the acid metabolite are illustrated in Figures 6 and 7. In this study, 24 healthy subjects (age = 27 + 4.2 years; height = 174 + 6.5 cm; weight = 70 + 5.8 kg) received 200 pg (one 200 ~g Cytotec tablet) and-400 pg (two 200 ~g Cytotec tablets) in the morning under fasting conditions in a randomized, crossover study. The washout period between the two treatments was 3 days. Blood samples were taken at frequent intervals for up to 4 hours after dosing for measurement of misoprostol acid plasma levels by the RIA method. Increasing the misoprostol dose from 200 to 400 ~g resulted in an approximately two-fold increase in the plasma levels of the acid metabolite: Cmax increased from 397 + 143 to 835 + 385 pg/ml (p<0.05) while AUC(0-4) increased from 205 + 94 to 392 + 156 pg.hr/ml (p<0.05). These findings not only confirmed the accuracy of the RIA method for


PROSTAGLANDINS

Fig. 6.

1800-

1600-

1400 -

1200"

' ~ t 000 -

6 0 0 -

4 0 0 -

2 0 0 -

Fig. 7.

,-. 1000 1

: 600

0

400 oo

~ 2O0 -

0 3 4

% l 2

Time, hrs

Mean plasma concentration-time curves of misoprostol acid following administration of single oral doses of 200 ~g ([]) and 400 ~g (o) of misoprostol to 24 subjects.

l A

900 -

8 0 0 -

? 0 0 -

6 0 0 - J :

. GO0-

1

4 0 0 -

. <

300 -

200 -

100-

397 (148) 835 (385) 205 (94) 392 (158) ' O - i i l

200 ~ g 400 lzg 200 ~ g 400 ~ g

Individual and mean (SD) values for Cmax and AUC(0-4) for misoprostol acid in 24 subjects who received single oral doses of 200 vg and 400 ~g of misoprostol.


PROSTAGLANDINS

measuring misoprostol acid but also established dose proportionality in the 200-400 ~g misoprostol dose range.

BIOAVAILABILITY OF MISOPROSTOL TABLETS RELATIVE TO ORAL SOLUTION

The oral bioavailability of misoprostol from commercial tablets (Cytotec tablets) relative to an oral solution was also assessed in the above 24 healthy subjects in a crossover study. Plasma misoprostol acid concentration- time curves and individual values for Cmax and AUC are given in Figures 8 and 9. Each subject received two 200 ~g of commercial Cytotec tablets and 400 ~g of misoprostol HPMC dispersion in solution. The washout period, blood sampling schedule, and assay method were the same as above. Figures 8 and 9 show that the absorption profile of misoprostol from commercial tablets or HPMC dispersion-solution was indistinguishable. Cmax values with solution and tablets were 828 + 378 and 835 + 385 pg/ml (p=N.S.), respectively, while-the AUC values were 396 + 162 and 392 + 156 pg.hr/ml (p=N.S.), respectively.

PLASMA LEVELS OF MISOPROSTOL FOLLOWING SINGLE AND MULTIPLE DOSES

Steady-state plasma concentrations of misoprostol acid were evaluated in 12 healthy subjects (age = 28 + 4.8 years; height = 173 + 8.6 cm; weight = 70 + 4.7 kg). Each subject received 400 ~g of misoprostol ql2h for 4 days under fasting conditions. Predose (minimum) and 10-minute (approximately peak) blood samples were taken on days 2 and 3 while frequent blood samples during each 12-hour dose interval were taken on days 1 and 4.

Predose and 10-minute plasma level data showed that steady-state conditions were established by day 2. Mean plasma concentration-time curves on days 1 and 4 are shown in Figure i0 and individual values for misoprostol acid Cmax and AUC(0-12) values are given in Figure ii. The elimination tl/2 of misoprostol acid on days 1 and 4 are shown in Figure 12. Following the first 400 ~g dose the mean + SD Cmax, AUC(0-12), and tl/2 values were 634 113 pg/mlT 353 + 82 pg.hr/ml, and 26.9 + 12.1 min, respectively, while at steady state on Nay 4 these values were 688 + 268 pg/ml, 294 + 87 pg.hr/ml, and 17.6 + 7.1 min, respectively. No statistical difference between the day 1 and day 4 values occurred in any of these pharmacokinetic parameters. There was thus neither any accumulation nor changes in pharmacokinetic parameters of misoprostol acid following multiple doses of misoprostol.


PROSTAGLANDINS

Fig. 8.

1800-

1000-

1400-

1 2 0 0 "

" ~ 1000- m_

8 0 0 -

600-

400-

200-

o-

Fig. 9.

1 0 0 0 1

8oo- 1

• " 600 - o

o

4 0 0 -

7~ ~ 2 0 0 -

O [ ' ~

0 3 4 , T 1 2

Time, h r s Mean plasma concentration-time curves of misoprostol acid in 24 subjects following single 400 ~g oral doses of misoprostol given as two 200 ~g commercial tablets (o) and an HPMC solution (Q).

( [ ' ~ ) 1 0 0 0 - ( [ ' ~ )

9 0 0 -

0 0 0 -

7 0 0 -

0 0 0 -

. ~ 000 -

T 400 -

3 0 0 -

2 0 0 -

100-

oz8 (378) 8z5 (z85) z9e 0ez) zgz 058) 0 - ' ' '

400/~g 400 ~zg 400/zg 400/~g Solution Tablets Solution Tablets Individual and mean (SD) values for Cmax and AUC(0-4) for misoprostol acid in 24 subjects who received single 400 ~g oral doses of misoprostol as two 200 ~g commercial tablets and an HPMC solution. N.S. = not significant.

4 8 S U P P L E M E N T T O V O L . 33

PROSTAGLANDINS

voo ~ Day 1 - oool

0

Fig. i0.

1 4 0 0 -

1200 -

I000-

~ , 8 0 0 - ~B

6 0 0 - ¢.3

4 0 0 -

2 0 0 -

O- r

Fig. II.

Day 4

73 74 75 76

Mean + SE plasma concentration-time curves of misoprostol acid in 12 subjects on days 1 and 4 following 400 ~g of misoprostol ql2h.

8 0 0 .

7 0 0 -

6 0 0 -

5 0 0 -

I

~ 3 0 0 -

i 2 3 4 72

T i m e , h r s

200-

1 0 0 -

ca4 (,is) eaa (2aa) a~a (92) 294 (sT) ' ' '~ ' . . . . . . . ' 0 i i r

Day I Day 4 Day 1 Day 4

Individual and mean (SD) values for Cmax and AUC(0-12) for misoprostol acid in 12 subjects on days 1 and 4 following 400 ~g of misoprostol ql2h. N.S. = not significant.


PROSTAGLANDINS

60-

Fig. 12.

5 0 -

4 0 -

. 3 0 -

2 0 -

IO-

zo.9 0z.1) 17.o (7a) 0 1 I I I

Day 1 Day 4

Individual and mean (SD) elimination half-lives (tl/2) of misoprostol acid in 12 subjects on d a y s 1 a n d 4 f o l l o w i n g 400 gg o f m i s o p r o s t o l ql2h. N.S. = not significant.


antiulcer prostaglandin misoprostol: single and multiple dose pharmacokinetic profile

Documents