ANTnImiCROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1978, p. 801-806 0066-4804/78/0014-0801$02.00/0 Copyright ©) 1978 American Society for Microbiology

Vol. 114, No. 6 Printed in U.S.A.

Phannacokinetics of Mezlocillin in Healthy Volunteers TOM BERGAN Department of Microbiology, Institute of Pharmnacy, Oslo 3, Norway Received for publication 8 September 1978

Mezlocillin in doses of 1.0, 2.0, and 5.0 g and carbenicillin in doses of 2.0 g were given as bolus injections intravenously to 10 healthy volunteers. For mezlocillin, dose-dependent pharmacokinetics was detected. This is reflected by a more than proportional rise in serum concentrations and a decreased total body clearance as doses were increased. Per dose unit, the areas under serum concentration curves to infinity were 33.5 ,g.h/ml for the 1.0-g dose, 47.2 ,ug.h/ml for the 2.0-g dose, and 54.8 ,Lg.h/ml for the 5.0-g dose. The body clearance fell from 31.2 liters/h with the 1.0-g dose to 17.0 liters/h with the 5.0-g dose. This can be explained mainly by a marked depression of nonrenal clearance, which fell from 12.2 to 3.8 liters/h, compared with a parallel change in renal clearance from 19.0 to 13.2 liters/h. Contributing to the non-linearity may be biotransforination, evacuation via bile, or another process. With dose increments, rising amounts are recovered unchanged in the urine-61% after a 1.0-g dose compared with 69% after a 5.0-g dose. This clearly defines metabolism as a major factor of elimination. Carbenicillin, for which the first-order, two-compartment open model was applicable here as in previous studies, had a longer serum half-life than did mezlocillin. For the 2.0-g doses, the former had a half-life of 1.4 h, compared with 0.8 h for the latter (calculated as if the two-compartment model were fully valid). The relative area ih/ml after the 2.0-g dose. under the curve (see above) was 76.1 ug the phannacokinetic properties of mezlocllin in healthy volunteers.

Mezlocillin (BAY f 1353) is a new semisynthetic ureidopenicillin with an antibacterial spectrum which appears to be wider than that of ampicillin, carbenicillin, mecillinam, and several cephalosporins (2, 7,10; H. B. Konig, K. Metzger, H. A. Offe, and W. Schrock, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 14th, San Francisco, Calif., Abstr. no. 371 and 372, 1974; C. Krasemann, 16th ICAAC, Chicago, Ill., Abstr. no. 346, 1976; K. Metzger, 15th ICAAC, Washington, D.C., Abstr. no. 332,1975). Of interest is its activity against Escherichia coli, some Klebsiella spp., some Enterobacter spp., many Serratia spp., indole-negative and some indole-positive Proteus spp., Haemophilus influenzae, gram-positive cocci including enterococci (Krasemann, 16th ICAAC, Abstr. no. 346; Metzger, 15th ICAAC, Abstr. no. 332), and anaerobes like Bacteroides and Clostridium (7, 10). A level of 32 ,tg/ml has been used as upper limit for mezlocillin sensitivity (Bayer AG, personal communication). It is more active in attainable therapeutic concentrations against Pseudomonas aeruginosa than is carbenicillin (Metzger, 15th ICAAC, Abstr. no. 332), although against this species another new ureidopenicillin, azlocillin, is even more active (Metzger, 15th ICAAC, Abstr. no. 332). The purpose of this study was to investigate

MATERIALS AND METHODS Subjects. Ten healthy volunteers, aged 22 to 29 years and with a mean weight of 73.5 kg (range, 66 to 85 kg), participated in the investigation. They had no episodes of allergy and were healthy as determined by clinical examination, hemoglobin, erythrocyte sedimentation rate, serum bilirubin, serum alkaline phosphatase, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, lactate dehydrogenase, triglycerides, cholesterol, serum iron, Na, K, Cl, and urinalysis in respect to glucose, protein, blood, and ketones. Informed consent was given, and the subjects were insured during the investigation against possible mishaps. Measures were at all times taken to meet possible acute reactions to the drug. Drug. Solutions (10%) of mezlocillin for intravenous use (batches 382114 and 382125) were prepared in pyrogen-free, sterile water. Doses of 1.0, 2.0, and 5.0 g were given. Carbenicillin (Fugacillin Astra; batch AK 23) was also prepared in a dose of 2.0 g. Both drugs were given as 10% solutions intravenously as bolus injections during 4 to 5 min. All subjects received all doses. The mezlocillin was kindly supplied by Bayer AG, Wuppertal, West Germany, and carbenicillin was supplied by Norsk Medisinaldepot, Oslo, Norway. Samples. Blood samples were withdrawn from an arm vein either by puncture or by an indwelling catheter at 5, 10, 15, 22.5, 30, 45, and 60 min as well as 1.5, 801

802

BERGAN

2, 3, 4, 5, 6, and 8 h after the dose was given. Urine was sampled during the following periods: 0 to 2, 2 to 4, 4 to 6, and 6 to 8 h. The urine samples taken after carbenicilhin treatment were unfortunately lost during storage. The blood was separated with 1 h, and serum was stored at -20°C before assay which was within 1 to 2 weeks. Assays. Antibiotic assays were done with an agar well procedure similar to one used previously (1). E.

coli 14 obtained from Bayer AG served as the test organism. For standards, mezlocillin from Bayer AG and carbenicillin from Astra Lakemedel AB, Sweden, both of certified potency, were used. Standards were made in pooled human serum and frozen together with samples. The accuracy of the assay is exemplified by reproducibility tests at 20,g of mezlocillin per ml; in these tests 20 samples had a mean of 19.95 ± 1.04

ANTIMICROB. AGENTS CHEMOTHER.

E z

0 Z.

0 z C)

,g/ml. Pharmacokinetics. Pharmacokinetic evaluation was performed by using the computer program AUTOAN 2/NONLIN of Sedman and Wagner/Metzler (8). After polyexponential curve fitting this program chooses the pharmacokinetic model which gives the best fit. For the intravenous bolus mezlocillin data, the first-order two-compartment open model was consistently selected. The program yields the basic parameters k12 (rate constant for transfer from the central to the peripheral compartment), k21 (rate constant for transfer from the peripheral to the central compartment), kE (rate of elimination from the central compartment), and co (sum of hybrid y-axis intercepts). These were automatically fed into a program from Norsk Regnesentral to estimate the polyexponentials and basic derived pharmacokinetic parameters, as commonly defined (6, 8). Statistical analysis of significance followed the Wilcoxon nonparametric test (9).

RESULTS Serum concentrations. Mean serum concentrations and the variance are presented in Fig. 1 and Table 1, respectively. There was relatively little variation among individuals. After a 2.0-g dose, the carbenicillin curve during the entire course was above that of mezlocillin. There was a linear relationship between the doses of mezlocillin and the total area under the curves to infinity (Fig. 2). However, the relative areas under the serum curves (F/total area under curve/dose) both the 2.0-g doses were significantly higher than that after the 1.0-g dose (P < 0.01). The fact that increased doses gave more than proportional rise in serum concentrations is apparent from Fig. 3. The relative serum concentrations after doses of 1.0 and 5.0 g were significantly different for the entire observation period (P < 0.01). The same applies for 2.0- and 5.0-g doses after the first 45 min. The 2.0-g levels differed from the- 1.0-g levels for the first 2 h. Urine recovery. The mezlocillin recovered unchanged in the urine is recorded in Table 2. Relatively more was excreted as the doses were increased, with means ranging from 61 to 69% of

U)

HOURS

1

2

3

4

5

6

7

8

FIG. 1. Mean serum concentration curves after intravenous bolus injections of 2.0 g of carbenicillin and 1.0, 2.0, and 5.0 g of mezlocillin to 10 healthy volunteers.

the total doses. Some 50 to 60% of the dose was excreted during the first 2 h. The mean half-life based on renal excretion was 0.7 h for the 1.0-g dose and 0.82 h for both the 2.0- and 5.0-g doses. Pharmacokinetics. The hybrid intercepts and plasma disposition constants of the distribution phase (A and a, respectively) and the elimination phase (B and I), respectively) are shown in Table 3. The total body clearance (CIB), renal clearance (CIR), and metabolic clearance (ClM) (i.e., sum of nonrenal mechanisms) are shown in Table 4. All decreased with increasing doses. The decrease in CIB was reflected by a pronounced reduction in the clearance due to nonrenal processes; the reduction in CIR was quite a bit less than than in ClM. ClB was lower for a 2.0-g dose of carbenicillin than for a 2.0-g dose of mezlocillin (P < 0.01). A very important finding was that CIB of mezlocillin decreased significantly with dose increments. There was a slight reduction in CIR, but the main reason was a marked reduction in clearance due to metabolism and possibly other extrarenal processes. CIR was 19.2 liters/h (317.0 ml/min) for the 1.0-g dose and 13.6 liters/h (219.0 ml/min) for the 5.0g dose. Correspondingly, ClM fell from 12.2 to 3.8 liters/h.

MEZLOCILLIN PHARMACOKINETICS

VOL. 14, 1978

803

lO

uli

L

LO

v

°V

°V

°V

°°

250

A MEZLOCILLIN 0 CARBENICILLIN

.S .-_i o. oi o4 .eIN_ .

-. -

o

es

200 [

E

0

0

> 150 LA.

GD

1-

6;

o

t-

In

*q'

N

L-

Co

CO

_

:t1D

Is

CD IL) .0

:3

Eu GP

GD

.1

I_

0

lit- 00

9c

50k

Gs

--

1-

GD

C

Lq ,-4

co" 5.I

4

4G

U-J

1-

I-

r-4

-.,C'

CD

GD

_q eq

0

C9 (3 L6t: -,

.0

,

LO

$

-CD

X

I" CD m M" M LL-3 LO

N' "-4 LO C64 '.4 -.-,M-, 8 .

.

.

--.,

".4

.

1

1-4

2

3

4

5

Dose, D (gram)

--.,

FIG. 2. Dose response of meziocillin. Relationship between dose and area under the serum concentration versus time curve.

i

L. e

O~ Cq

eu

?

C'

mD0

q

-

asan

10

tzC' t6

a

: -:

._D

H4 ce 1tq

q

CO

UIO

r"

41Ui P'to

0

9l

1-

id

0D

1

4 0

= c a 50

.G

D.

i 0

C; la

2

a

In view of the pattern of dose-dependent clearand areas under the serum curves, we will limit the documentation mainly to dose-independent parameters. The individual serum concentration curves do not deviate much from a bi-exponential course because drug disposition is not severely nonlinear and elimination is quite rapid. Hybrid intercepts and plasma disposition constants for the predominantly distributive phase (A and a) and of the predominatly eliminatory phase (B and fB) are shown in Table 3. The serum half-life of the 2.0-g dose of carbenicillin was 1.40 + 0.32 h, corresponding to a rate constant of elimination from the central compartment, kE, of 1.498 ± 0.181 h-1, calculated on the basis of the twocompartment open model. For comparison only, the half-life for the mezlocillin doses are shown in Table 4. There were no statistical differences for a, f,, or half-life after each dose. The distribution volumes for the central compartment appear in Table 4. ances

0

.0

DISCUSSION Most unusual, considering that it pertains to a penicillin, is the finding that mezlocillin has dose-dependent pharmacokinetics. The normal-

804

BERGAN

ANTIMICROB. AGENTS CHEMOTHER.

ized serum curves are not completely superimposable (Fig. 3), and the rise in serum concentrations is more than proportional to dose increments. This is primarily due to non-linearity of extrarenal process(es), as reflected by the particular reduction in ClM. There is a parallel decline in CIR, but this is not as marked. The source is most likely biotransformation, i.e., saturable enzyme activity (Michaelis-Menten kinetics), perhaps related to breakdown of the long alphaposition side chain, although other processes may also be considered. The relatively low relOOr -

\'A5

cm

_*

=1

_o

=

2g

.a

=

3g

.b

1-

LLJ (n

\

8l

4. \\

C-)

\.

0

'' 0

&o '.sK

z

z

0

m"a-\~~~~~~~~~~~~~~.I"

1

n)

I

oxN

011_ *0

1

2

3 4 TIME, hours

5

FIG. 3. Relative serum concentrations after doses of 1.0, 2.0, and 5.0 g of mezlocillin, normalized to a dose of 1.0 g.

of unchanged drug in the urine indicates directly that a large portion of the compound is, indeed, metabolized. The higher percentage of unchanged drug also reflects the extent of the rate-limited biotransformation. As the dose is increased from 1.0 to 5.0 g, 8% escapes biotransformation. It is notable that after the 2.0-g doses carbenicillin, for which only the normal firstorder, two-compartment open model has been published, has a lower body clearance and consequently longer half-life than does mezlocillin. The low urinary recovery could also reflect biliary excretion. In subjects with a healthy hepatobiliary system, about 25% of the 2.0-g mezlocillin dose has been recovered in bile (8 h) (Gundert, Forster, and Schacht, personal communication). Substance entering the gut is probably not reabsorbed, because sub-detectable levels have been obtained after acid-resistant capsules were given orally (Bayer AG, personal communication). Biliary excretion may in itself be rate limited. Chemically, carbenicillin and mezlocillin are different in their alpha-position side chains, but otherwise they are similar in a number of properties, such as protein binding (ca. 50% [4; Bayer AG, personal communication]), pKa (2.6 and 2.8, respectively, at physiological pH), and lipid solubility. The molecular weight is 580 for mezlocilhin and 422 for carbenicillin. It is notable that the ratio of the areas under the serum curves after 2.0-g doses approximately equals the inverse of the ratio of the molecular weights of the compounds, but this may be coincidental. The pharmacokinetic properties of the two compounds are not in themselves indicative of a superior therapeutic potential for either compound. Lower mezlocillin concentrations might appear permissible by virtue of its higher antibacterial activity against many gram-negatives (e.g. Bacteroides spp., Pseudomonas aeruginosa, Proteus spp.). This is counterbalanced by the higher carbenicillin levels after equal doses. covery

TABLE 2. Urine excretion of mezlocillin after bolus doses were given intravenously % Mezlocillin excreted in the following time periods Total excreted

Dose (g)

0-2h 1.0 2.0 5.0

24h

55.4

4.3

(15.0%

(1.7)

60.0 (15.1) 60.1 (10.4)

5.9 (2.8) 7.0 (2.2)

'Values in parentheses are standard deviations. b ND, Not done.

4-6h 1.03 (1.23) 1.27 (0.80) 1.52 (0.52)

6-8hh% NDb

ND

0.35 (0.21) 0.35 (0.12)

60.8 (13.5) 67.0 (16.3) 69.0 (12.1)

VOL. 14, 1978

MEZLOCILLIN PHARMACOKINETICS

805

TABLE 3. Kinetic characteristics of carbenicillin and mezlocillin given intravenously as bolus doses Dose Aa B a a9 Plasma Antibiotic (g)

(jg/ml)

(jAg/mi)

(h-1)

(h-I)

half-life

Carbenicilin

2.0

190.47b

63.18 (9.77)

4.355 (1.014)

0.522 (0.136)

1.40 (0.32)

Mezlociin

1.0

(57.90)

58.45 16.70 4.267 (19.50) (9.80) (1.288) 2.0 178.50 46.60 4.709 (41.00) (8.40) (1.083) 5.0 368.06 99.03 3.336 (73.45) (32.55) (0.994) a Symbols are explained in the text. b Values given are means and, in parentheses, standard deviations.

(h)

0.911

0.96

(0.555) 0.914 (0.193) 0.629

(0.41) 0.79 (0.16) 1.21

(0.172)

(0.45)

TABLE 4. Area under the serum curve, central distribution volume CIB, CIR, and CIM Antibiotic Antibiotic

Carbenicillin Mezlociflin

I)Dose o(g) 2.0

F0 (jAg.h/ml) 152.22b

Vc

(liters)

CIB

(liters/h) 12.27

(liters/h)

CIR

CiM (liters/h)

12.2 (4.1) 6.9 (1.9)

(55.36)

8.32 (2.35)

2.0

33.54 (7.20) 94.43 (14.43)

13.64 (2.38) 9.08 (1.59)

(3.03) 31.24 (7.57) 21.08 (4.47)

19.02 (6.11) 14.20 (3.42)

5.0

274.10

10.04

16.96

13.16

3.8

(31.64)

(3.70)

(5.72)

(3.46)

(1.3)

1.0

a Abbreviations: F, area under the serum curve; Vc, central distribution volume. Other abbreviations are defined in the text. ClB5 kEVC; CIR = amount in urine/area under plasma curve; ClM = CIB - CIR. b Values given are means and, in parentheses, standard deviations.

In view of the fact that the break point for mezlocillin sensitivity has been set at 32 ,ug/ml, it is noted that levels are maintained in serum only for some 2 h after the 5.0-g dose, for 0.85 h after the 2.0-g dose, and for about 15 min after the 1.0-g dose. Urine levels remain above that niveau for 6 to 8 hours regardless of dose. Because the drug has a fast distribution, dosage every 6 to 8 hours would be recommendable in most general infections. Dosage three times daily would probably suffice for urinary infections, at least if they are not complicated by tissue damage or reduced renal function. It would seem that 32 ,ug/ml is a realistic level for uncomplicated urinary tract infections. Strains with a minimal inhibitory concentration close to 32 ,ug/ml would seem to need 5.0-g doses, but this point requires clinical elaboration. It is to be noted, however, that the carbenicillin concentrations and pharmacokinetic characteristics are mainly in accordance with previous publications (4, 5), although our mezlocillin levels are lower than those observed by others (however, they are not statistically different [3; Bayer AG, unpublished data]). In adults smaller than those entering this study and more similar to those studied elsewhere, we have noted concentrations similar to those found by others

(unpublished data). The present mezlocillin levels are similar to those obtained for azlocillin (11). Comparing the same dose, the pharmacokinetic characteristics are in accordance with the findings of others (3). Lode et al. (3), after a 30min infusion of 5.0 g, found a half-life of 0.95 ± 0.17 h, compared with 1.21 + 0.45 h in this study. Lode et al. (3) recovered 53% unchanged drug in the urine during 6 h, compared with our 69% during 8 h after a 5.0-g dose. ACKNOWLEDGMENT The expert technical assistance of Mari

fully appreciated.

Vangdal is grate-

LITERATURE CITED 1. Bergan, T., and B. Oydvin. 1972. Microbiological assay of josamycin. Acta Pathol. Microbiol. Scand. Sect. B 80:101-106. 2. Bodey, G. P., and T. Pan. 1977. Mezlocillin: in vitro studies of a new broad-spectrum penicillin. Antimicrob. Agents Chemother. 11:74-79. 3. Lode, EL, U. Niestrath, P. Koeppe, and H. Langmack. 1977. Azlocillin und Mezlocillin: Zwei neue semisynthetische Acylureidopenicilline. Infection 5:163-169. 4. Otten, H., M. Plempel, and W. Siegenthaler. 1975. Antibiotika-Fibel, 4th ed. Georg Thieme Verlag, Stutt-

gart. 5. Palmer, W.-R. and D. Hoifier. 1977. Carbenicillin. Basisdaten zur Therapie mit einem Antibiotikum. Urban & Schwarzenberg, Miinchen.

806

BERGAN

6. Ritschel, W. A. 1976. Handbook of basic pharmacokinetics. Drug Intelligence Publications, Hamilton, Ill. 7. Sutter, V. L., and S. M. Finegold. 1976. Susceptibility of anaerobic bacteria to 23 antimicrobial agents. Antimicrob. Agents Chemother. 10:736-752. 8. Wagner, J. G. 1975. Fundamentals of pharmacokinetics. Drug Intelligence Publications, Hamilton, Ill. 9. Weber, E. 1972. Grundriss der biologischen Statistik. Gustav Fischer Verlag, Stuttgart.

ANTIMICROB. AGENTS CHEMOTHER. 10. Werner, H., C. Krasemann, J. Ungerechts, and H. J. Schmitz. 1977. Die in-vitro-Aktivitat von Mezlocillin, Azlocillin und Carbenicillin gegen Bacteroidaceae unter besonderer Beriicksichtigung der Fragilis-Gruppe. Infection 5:17-21. 11. Wirth, K., M. Schomerus, and J. H. Hengstmann. 1976. Zur Pharmakokinetik von Azlocillin, einem neuen halbsynthetischen Breitspektrumantibiotikum. Infection 4:25-30.

Pharmacokinetics of mezlocillin in healthy volunteers.

ANTnImiCROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1978, p. 801-806 0066-4804/78/0014-0801$02.00/0 Copyright ©) 1978 American Society for Microbiology Vol...
698KB Sizes 0 Downloads 0 Views