oral pharmacokinetics of omeprazole and lansoprazole after single and repeated doses as intact...

Oral pharmacokinetics of omeprazole and lansoprazoleafter single and repeated doses as intact capsulesor as suspensions in sodium bicarbonate

V. K. SHARMA*, B. PEYTON*, T. SPEARS*, J . -P. RAUFMAN* & C. W. HOWDEN *Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; and Division

of Gastroenterology and Hepatology, Northwestern University, Chicago, IL, USA

Accepted for publication 13 March 2000

INTRODUCTION

The proton pump inhibitors omeprazole and lansopra-

zole are generally administered orally as capsules of

enteric-coated granules. However, patients with swal-

lowing disorders and those with indwelling gastrostomy

or nasogastric feeding tubes may be unable to take these

proton pump inhibitor formulations by mouth. We have

previously shown that both omeprazole and lansopraz-

ole are effective in suppressing intragastric acidity when

administered through a gastrostomy tube as intact,

non-encapsulated granules in orange juice.1, 2 Degrees

of suppression of acidity were comparable to those

reported by others for the intact capsule formulations of

omeprazole and lansoprazole.3, 4 However, there may

be a reluctance to administer intact granules of a proton

pump inhibitor through a feeding tube because of

perceived dif®culties with aggregation of granules and

tube blockage. Although we did not encounter these

SUMMARY

Background: Omeprazole and lansoprazole can be given

in sodium bicarbonate as, respectively, simpli®ed omep-

razole suspension and simpli®ed lansoprazole suspen-

sion. We previously found the antisecretory effect of

omeprazole 20 mg given as simpli®ed omeprazole

suspension to be lower than with intact capsules.

However, lansoprazole 30 mg as simpli®ed lansoprazole

suspension produced an effect similar to that seen

with intact capsules.

Aim: To evaluate the absorption of both drugs when

given orally as capsules or as suspensions in sodium

bicarbonate.

Methods: In random order, we gave 5-day courses of

omeprazole 20 mg and lansoprazole 30 mg as capsules

and as suspensions in sodium bicarbonate to 12

healthy women. Serial blood samples were taken on

days 1 and 5 of each course for pharmacokinetic

measurements.

Results: There was impairment of omeprazole absorp-

tion when given as simpli®ed omeprazole suspension.

Maximum plasma concentration and area under the

concentration/time curve were lower with simpli®ed

omeprazole suspension than with omeprazole capsules

(P � 0.034 and 0.013, respectively, on day 5). No

differences were found in lansoprazole absorption when

simpli®ed lansoprazole suspension was compared with

its standard capsule formulation. Relative bioavailability

of omeprazole from simpli®ed omeprazole suspension

compared to the capsule was 58.4% on day 5. The

corresponding value for lansoprazole was 84.7%.

Conclusions: Simpli®ed omeprazole suspension 20 mg

does not supply adequate omeprazole for systemic

absorption. Lansoprazole absorption from simpli®ed

lansoprazole suspension is maintained.

Correspondence to: Dr C. W. Howden, Northwestern University,

Northwestern Center for Clinical Research, 680 N. Lakeshore Drive,

Suite 1220, Chicago, IL 60611, USA.E-mail: [email protected]

Aliment Pharmacol Ther 2000; 14: 887±892.

Ó 2000 Blackwell Science Ltd 887

problems in our studies, we subsequently evaluated the

effectiveness of omeprazole and lansoprazole as suspen-

sions in 8.4% sodium bicarbonate.1, 2 These were

termed, respectively, simpli®ed omeprazole suspension

and simpli®ed lansoprazole suspension. The per-gas-

trostomy administration of simpli®ed lansoprazole sus-

pension raised intragastric pH to levels that were

comparable to those seen with the intact capsule

formulation of lansoprazole.5 However, simpli®ed omep-

razole suspension administered through a gastrostomy

had an effect on intragastric pH that was quantitatively

smaller than that observed with either intact omepraz-

ole capsules or intact, non-encapsulated omeprazole

granules in orange juice.6

Little is known about the absorption of either omep-

razole or lansoprazole when administered as a suspen-

sion in sodium bicarbonate. In one study, an oral

suspension of lansoprazole granules in a ¯avouring

solution produced comparable plasma levels to those

seen with the administration of intact lansoprazole

capsules.7 The administration of intact lansoprazole

granules orally in apple sauce, or via a nasogastric tube

in apple juice, produces plasma lansoprazole levels that

are comparable to those seen with the intact capsule.8, 9

The absorption of omeprazole from its standard capsule

formulation displays marked inter- and intra-individual

variability.10 Furthermore, the proportion of the omep-

razole dose that is absorbed increases with repeated

once daily administration to reach a plateau by the 5th

day.10±12 However, the bioavailability of lansoprazole

does not progressively increase with repeated daily

dosing, being near maximal after a single dose.13, 14

We conducted this study to compare the absorption

characteristics of each proton pump inhibitor when

administered after single and repeated once-daily dos-

ing, as intact capsules and as suspensions in sodium

bicarbonate.

MATERIALS AND METHODS

Twelve healthy women were recruited for the study.

Their mean (� s.d.) age was 36.8 (� 9.8) years, their

mean (� s.d.) weight was 73.6 (� 12.7) kg and their

mean (� s.d.) height was 1.66 (� 0.07) m. None had

any signi®cant past medical history of note and none

was taking any regular prescribed medication. None

had received either omeprazole or lansoprazole in the

preceding month. Each subject gave her written,

informed consent to the study, which was approved

by the institutional review board of the University of

Arkansas for Medical Sciences, Little Rock, AR.

All studies were performed in the Division of Gastro-

enterology, University of Arkansas for Medical Sciences,

Little Rock, AR. In a pre-determined random order,

subjects received each of four proton pump inhibitor

formulations once daily for 5 days. The dosing periods

were separated by 9-day washout periods. The four

formulations studied were intact omeprazole capsules

20 mg, simpli®ed omeprazole suspension 20 mg, intact

lansoprazole capsules 30 mg and simpli®ed lansoprazole

suspension 30 mg. These were taken at 08.00 hours on

each day, 30 min before the ®rst food of the day and

after an overnight fast. Study drugs were administered

in this way to mimic, as far as was reasonably possible,

the manner in which proton pump inhibitors are

usually prescribed.

On the ®rst and ®fth days of dosing, subjects had serial

blood sampling for plasma drug levels. An intravenous

cannula was inserted into an arm vein and 10 mL blood

samples were withdrawn at 0, 0.5, 1, 1.5, 2, 2.5, 3 and

6 h after dosing for, as appropriate, plasma omeprazole

or lansoprazole levels. Subjects were observed during

these times in a specialized clinical investigation unit.

Subjects had a standard breakfast 30 min after dosing

and had nothing further by mouth until the conclusion

of the study. Blood samples were collected into tubes

containing heparin sodium and centrifuged at

2500 r.p.m. for 15 min. Plasma was decanted and

samples stored at )20 °C until being shipped in batch at

the conclusion of the study to Harris Laboratories

(Lincoln, NE) for analysis.

Lansoprazole (internal standardÐomeprazole) and

omeprazole (internal standardÐlansoprazole) were

extracted from heparinized plasma into ethyl ether:

methylene chloride, 70:30 (v:v). The extracts were dried

under nitrogen and reconstituted in acetonitrile and

injected into an on-line LC/MS/MS system. Detection of

the analytes was performed with an Inertsil silica

column and a Perkin-Elmer API 365 tandem mass

spectrometer using a turbo ion spray interface. Positive

ions (m/z of 370.2±> 251.9 for lansoprazole and

346.2±> 198.1 for omeprazole) were monitored in the

MRM mode.

We have previously described the methods for the

preparation of simpli®ed omeprazole suspension and

simpli®ed lansoprazole suspension.5, 6 Brie¯y, these

were prepared by opening a 20-mg omeprazole capsule

or a 30-mg lansoprazole capsule, pouring the granular

888 V. K. SHARMA et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 887±892

contents into 10 mL of 8.4% sodium bicarbonate

(pH 7.8; osmolality 20 mOsm/mL) and gently mixing

until the contents were suspended. The resulting milky

white liquid was then administered by mouth. The

suspensions were freshly prepared for each administra-

tion during this study. The pH of simpli®ed omeprazole

suspension was 7.97; the pH of simpli®ed lansoprazole

suspension was 7.92.

Using a 10-cm visual analogue scale, subjects were

asked to rate the palatability of each of the four

formulations administered on day 1 and day 5. On this

scale, zero indicated the worst imaginable taste and 10

the best.

Statistical analysis

Plasma omeprazole and lansoprazole levels were tabu-

lated for each subject. Maximum plasma concentration

(Cmax) and time to Cmax (tmax) were derived from

inspection of the data. The area under the plasma

concentration/time curve (AUC) was calculated accord-

ing to the linear trapezoidal rule.

Data for tmax, Cmax and AUC were summarized as

medians and ranges, and analysed non-parametrically.

Values for tmax, Cmax and AUC with omeprazole capsules

were compared to those with simpli®ed omeprazole

suspension using the Wilcoxon matched-pairs signed-

rank test. Corresponding data for lansoprazole and

simpli®ed lansoprazole suspension were handled simi-

larly. Omeprazole data were not compared with lan-

soprazole data. Data for tmax, Cmax and AUC for each

formulation on day 1 of its administration were

compared with those on day 5 of administration. The

relative bioavailability of omeprazole from simpli®ed

omeprazole suspension and of lansoprazole from

simpli®ed lansoprazole suspension was de®ned as

AUCsuspension/AUCcapsule..7 Data on palatability between

the suspensions and capsules were compared using the

paired Student's t-tests. All tests were two-tailed;

P-values of 0.05 or lower were considered statistically

signi®cant.

RESULTS

Each subject completed all four dosing schedules. No

adverse events were reported during dosing with

omeprazole or lansoprazole, either as intact capsules

or as suspensions. For both omeprazole and lansopraz-

ole, each subject preferred the intact capsule formula-

tion to the liquid suspension in sodium bicarbonate

(P < 0.001 for each comparison).

Omeprazole and simpli®ed omeprazole suspension

Table 1 lists the summary pharmacokinetic data for

omeprazole when given as intact capsules and as

simpli®ed omeprazole suspension. There was no signi-

®cant change in tmax between days 1 and 5 of dosing

with either omeprazole capsules or simpli®ed omepraz-

ole suspension. However, tmax on simpli®ed omeprazole

suspension was signi®cantly lower than on omeprazole

capsules at day 1 (P � 0.03) but not at day 5

(P � 0.075). During dosing with omeprazole capsules,

Cmax and AUC were signi®cantly higher on day 5 than

on day 1 (P � 0.041 and 0.003, respectively). How-

ever, there was no signi®cant difference for Cmax or

AUC, comparing days 1 and 5 of simpli®ed omeprazole

suspension administration (P � 0.388 and 0.093,

respectively).

On day 5, Cmax after standard omeprazole capsules was

signi®cantly higher than with simpli®ed omeprazole

suspension (P � 0.034), although no signi®cant differ-

ence was seen on day 1 (P � 0.158). AUC was higher

after standard omeprazole capsules than after simpli®ed

Table 1. Summary pharmacokinetic data expressed as median (range) following omeprazole 20 mg o.d. as capsules and as simpli®ed

omeprazole suspension

Omeprazole capsules 20 mg SOS 20 mg

Day 1 Day 5 Day 1 Day 5

tmax (h) 1.0 (0.5±6) 1.25 (0.5±2) 0.5a (0.5±1.5) 0.5 (0.5±1.5)

Cmax (ng/mL) 222 (56±676) 430b,c (74±1100) 172 (69±393) 198 (69±800)

AUC (ng.h/mL) 197d (76±1220) 454e,f (126±1423) 160 (88±838) 265 (81±1331)

SOS, simpli®ed omeprazole suspension.aP = 0.03 vs. omeprazole capsules, day 1; bP = 0.041 vs. omeprazole capsules, day 1; cP = 0.034 vs. SOS, day 5; dP = 0.037 vs. SOS, day 1;eP = 0.003 vs. omeprazole capsules, day 1; fP = 0.013 vs. SOS, day 5.

PROTON PUMP INHIBITOR PHARMACOKINETICS 889


omeprazole suspension on day 1 (P � 0.037) and day 5

(P � 0.013).

The relative bioavailability (95% CI) of omeprazole

from simpli®ed omeprazole suspension compared to the

capsule was 81.2% (59.1±103.3%) on day 1 and 58.4%

(30.5±86.3%) on day 5.

Lansoprazole and simpli®ed lansoprazole suspension

Summary data for tmax, Cmax and AUC on days 1 and 5

of dosing with standard lansoprazole capsules and

simpli®ed lansoprazole suspension appear in Table 2.

There was no signi®cant change in tmax between days 1

and 5 of dosing with either standard lansoprazole

capsules (P � 0.527) or simpli®ed lansoprazole suspen-

sion (P � 0.102). On day 1, tmax was signi®cantly lower

with simpli®ed lansoprazole suspension than with the

standard capsule formulation (P � 0.003), although no

signi®cant difference was seen between the two formu-

lations on day 5 (P � 0.073). Between days 1 and 5 of

dosing with standard lansoprazole capsules, no signi-

®cant difference was found for Cmax (P � 0.695) or AUC

(P � 0.638). For simpli®ed lansoprazole suspension,

Cmax on days 1 and 5 was not signi®cantly different

(P � 0.158), although there was a tendency for AUC to

increase (P � 0.050).

On day 1, there was no signi®cant difference between

standard lansoprazole capsules and simpli®ed lansop-

razole suspension for Cmax (P � 0.695) or AUC

(P � 0.075). Similarly, for day 5, Cmax and AUC values

were similar between standard lansoprazole capsules

and simpli®ed lansoprazole suspension (P � 0.195 and

1.00, respectively).

The relative bioavailability (95% CI) of lansoprazole

from simpli®ed lansoprazole suspension compared to the

capsule was 67.5% (41.0±94.0%) on day 1 and 84.7%

(64.3±105.1%) on day 5.

DISCUSSION

Consistent with other studies, we found an increase in

the degree of absorption of omeprazole when given in

repeated once daily doses as its standard capsule

formulation.10±12 However, we did not ®nd this when

we studied the pharmacokinetics of omeprazole admin-

istered as simpli®ed omeprazole suspension. Absorption

of omeprazole from this formulation was reduced in

comparison to that seen with the standard capsule

formulation and there was no signi®cant increase in the

degree of absorption seen with repeated once daily

dosing over 5 days. The AUC increased by day 5 only

for the standard capsule formulation of omeprazole and

not for simpli®ed omeprazole suspension. The absorp-

tion of omeprazole from its standard capsule formula-

tion increases progressively over the ®rst few days of

dosing because of a progressive inhibition of intragastric

acidity and a consequent increase in the amount of

omeprazole that is not denatured by acid and so is

available for absorption. That this does not happen

when omeprazole is administered in the form of

simpli®ed omeprazole suspension is probably explained

on the basis of the reduced gastric antisecretory effect of

simpli®ed omeprazole suspension compared to standard

omeprazole capsules, as we have previously reported.6

In contrast, lansoprazole was well absorbed when

given as simpli®ed lansoprazole suspension. Cmax and

AUC values after simpli®ed lansoprazole suspension

were comparable to those seen with the standard

capsule formulation of lansoprazole. Cmax and AUC did

not progressively increase over 5 days of dosing with

the intact capsule formulation of lansoprazole. As

reported by others, this indicates near maximal bio-

availability of lansoprazole within the ®rst day of oral

administration.13, 14 However, there was a quantita-

tively smallÐthough statistically signi®cantÐincrease

Table 2. Summary pharmacokinetic data expressed as median (range) following lansoprazole 30 mg o.d. as capsules and as simpli®ed

lansoprazole suspension

Lansoprazole capsules 30 mg SLS 30 mg

Day 1 Day 5 Day 1 Day 5

tmax (h) 1.0 (0.5±6) 1.5 (0.5±3) 0.5a (0.5±0.5) 0.5 (0.5±3)

Cmax (ng/mL) 678 (198±1588) 810 (80±1276) 791 (303±1370) 989 (484±1412)

AUC (ng.h/mL) 1342 (206±2542) 1109 (204±2549) 906 (350±2072) 939b (459±2408)

SLS, simpli®ed lansoprazole suspension.aP = 0.003 vs. lansoprazole capsules, day 1; bP = 0.05 vs. SLS, day 1.



in AUC seen between days 1 and 5 of dosing with

simpli®ed lansoprazole suspension (Table 2). By day 5,

the bioavailability of lansoprazole from simpli®ed lan-

soprazole suspension was similar to that seen with the

capsule formulation.

Phillips et al. have previously studied simpli®ed omep-

razole suspension in the prevention of stress-related

gastric bleeding in critically ill patients in an intensive

care unit.15 They administered two 40 mg doses of

simpli®ed omeprazole suspension on the ®rst day

followed by a daily 20 mg dose for the duration of their

study. These patients were not comparable to those in

our previous pharmacodynamic study of simpli®ed

omeprazole suspension.6 The former were critically ill

and had a high baseline intragastric pH while our

subjects were in a stable clinical condition without any

acute disease. These differences in study subjects,

experimental conditions and dosing schedules may

explain the different ®ndings from the two studies.

Presumably, the higher dose of simpli®ed omeprazole

suspension used in the study by Phillips et al. provided

suf®cient omeprazole for adequate systemic

absorption.15 However, our studies show that there is

insuf®cient absorption of omeprazole from simpli®ed

omeprazole suspension 20 mg. At the dose of 20 mg

o.d., simpli®ed omeprazole suspension may be

inadequate for routine clinical use as an inhibitor of

intragastric acidity.

CONCLUSION

Our current study has found differences between

simpli®ed omeprazole suspension and simpli®ed lansop-

razole suspension in terms of the degree of absorption of

their respective proton pump inhibitors when given by

mouth to healthy subjects. Lansoprazole absorption

from simpli®ed lansoprazole suspension is similar to that

seen with the standard capsule formulation, while the

absorption of omeprazole from simpli®ed omeprazole

suspension is impaired. Neither simpli®ed omeprazole

suspension nor simpli®ed lansoprazole suspension had

acceptable palatability when taken by mouth. However,

this would not be of relevance if administered through a

nasogastric or gastrostomy tube. Simpli®ed lansoprazole

suspension is at least as simple to prepare as simpli®ed

omeprazole suspension and has been shown to retain

over 90% stability when refrigerated for 4 weeks or

when stored at room temperature for 2 weeks.16 In a

dose of 30 mg o.d. through a gastrostomy, simpli®ed

lansoprazole suspension had a profound and consistent

effect on intragastric acidity.5 Since lansoprazole is well

absorbed when given as simpli®ed lansoprazole suspen-

sion, further study of this formulation in appropriate

clinical situations is certainly justi®ed.

ACKNOWLEDGEMENT

Financial support for this study was provided by TAP

Pharmaceuticals Inc., Deer®eld, IL, USA.

REFERENCES

1 Sharma VK, Heinzelmann EJ, Steinberg EN, Vasudeva R,

Howden CW. Nonencapsulated, intact omeprazole granules

effectively inhibit intragastric acidity when administered via a

gastrostomy. Am J Gastroenterol 1997; 92: 848±51.

2 Sharma VK, Ugheoke EA, Vasudeva R, Howden CW. The

pharmacodynamics of lansoprazole administered via gastros-

tomy as intact, non-encapsulated granules. Aliment Phar-

macol Ther 1998; 12: 1171±4.

3 Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE,

Ringham GL. The effects of oral doses of lansoprazole and

omeprazole on gastric pH. J Clin Gastroenterol 1997; 24:

65±70.

4 Chiverton SG, Howden CW, Burget DW, Hunt RH. Omepraz-

ole (20 mg) daily given in the morning or evening: a com-

parison of effects on gastric acidity and plasma gastrin and

omeprazole concentration. Aliment Pharmacol Ther 1992; 6:

103±11.

5 Sharma VK, Vasudeva R, Howden CW. Simpli®ed lansoprazole

suspensionÐa liquid formulation of lansoprazoleÐeffectively

suppresses intragastric acidity when administered through a

gastrostomy. Am J Gastroenterol 1999; 94: 1813±7.

6 Sharma VK, Vasudeva R, Howden CW. The effects on intra-

gastric acidity of per-gastrostomy administration of an alka-

line suspension of omeprazole. Aliment Pharm Ther 1999; 13:

1091±5.

7 Lochart SP, Baxter G. A lansoprazole suspension formulation

as an alternative to capsules for oral administration. Digestion

1998; 59: 226(Abstract).

8 Chun AH, Eason CJ, Shi HH, Cavanaugh JH. Lansoprazole:

an alternative method of administration of a capsule dosage

formulation. Clin Ther 1995; 17: 441±7.

9 Chun AH, Shi HH, Achari R, Dennis S, Cavanaugh JH. Lan-

soprazole: administration of the contents of a capsule dosage

formulation through a nasogastric tube. Clin Ther 1996; 18:

833±42.

10 Howden CW. Clinical pharmacology of omeprazole. Clin

Pharmacokinet 1991; 20: 38±49.

11 Howden CW, Meredith PA, Forrest JAH, Reid JL. Oral phar-

macokinetics of omeprazole. Eur J Clin Pharmacol 1984; 26:

641±3.

12 Howden CW, Forrest JAH, Meredith PA, Reid JL. Antisecretory

effect and oral pharmacokinetics following low dose omep-

razole in man. Br J Clin Pharmacol 1985; 20: 137±9.

PROTON PUMP INHIBITOR PHARMACOKINETICS 891


13 Flouvat B, Delhotal-Landes B, Cournot A, et al. Single and

multiple dose pharmacokinetics of lansoprazole in elderly

subjects. Br J Clin Pharmacol 1993; 36: 467±9.

14 Spencer CM, Faulds D. Lansoprazole: a reappraisal of its

pharmacodynamic and pharmacokinetic properties, and its

therapeutic ef®cacy in acid-related disorders. Drugs 1994; 48:

404±30.

15 Phillips JO, Metzler MH, Palmieri TL, Huckfeldt RE, Dahl NG.

A prospective study of simpli®ed omeprazole suspension for

the prophylaxis of stress-related mucosal damage. Crit Care

Med 1996; 24: 1793±800.

16 Phillips JO, Metzler MH. The stability of simpli®ed lansoprazole

suspension (SLS). Gastroenterology 1999; 116: A89(Ab-

stract).



oral pharmacokinetics of omeprazole and lansoprazole after single and repeated doses as intact...

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