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The Pharmacokinetics of Injectable Allopurinol in Newborns With the Hypoplastic Left Heart Syndrome

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The

Pharmacokinetics

of Injectable

Allopurinol

in Newborns

With

the

Hypoplastic

Left

Heart

Syndrome

Susan Phillips McGaurn, PharmD*; Lisa E. Davis, PharmD; Motria M. Krawczeniuk, PharmD;

John D. Murphy, MD; Marshall L. Jacobs, MD#; William I. Norwood, MD#; and Robert R. Clancy, MD*

ABSTRACT. Objective. The purpose of this investiga-lion was to determine the pharmacokinetic disposition of intravenous allopurinol and its metabolite oxypurinol in neonates with the hypoplastic left heart syndrome (HLHS) and to evaluate the subsequent degree of

xan-thine oxidase inhibition using serum uric acid as a

marker.

Methods. Pharmacokinetic data were evaluated in 12

stable preoperative neonates with HLHS after a single intravenous allopurinol administration of 5 mg/kg or 10

mg/kg. Pharmacokinetic parameters were determined for

elimination half-life, clearance, volume of distribution, and mean residence time. Xanthine oxidase inhibition, measured by serum uric acid reduction, was also mea-sured.

Results. Pharmacokinetic parameters revealed no

sta-tistically significant differences between a 5-mg/kg and 10-mg/kg dose of intravenous allopurinol on elimination half-life, clearance, volume of distribution, and mean residence time. Mean serum uric acid levels were signif-icantly reduced from baseline by 39.99 and 42.94%, re-spectively, in the 5- and 10-mg/kg treatment groups.

Discussion. The enzyme xanthine oxidase plays a key biochemical role in the generation of toxic

oxygen-de-rived free radicals during ischemia-reperfusion condi-tions. Allopurinol and its active metabolite oxypurinol

inhibit xanthine oxidase, and significantly reduce the conversion of hypoxanthine to xanthine and xanthine to uric acid. Cell injury may be caused by toxic oxygen free radicals produced by ischemia-reperfusion injury such as could occur during the repair of HLHS under hypother-mic total circulatory arrest. We hypothesize that allopuri-nol may provide protection from cellular injury in this clinical context. Pediatrics 199494:820-823; allopurinol,

ischemia-reperfusion, hypoplastic left heart syndrome,

hypothermic total circulatory arrest, neuroprotection,

pharmacokinetics.

ABBREVIATIONS. CHD, congenital heart disease; Cmax,

maxi-mum serum concentration; time to maximum serum

concen-tration; AUC, area under the serum concentration versus time curve; AUMC, area under the first moment curve.

PURPOSE

The purpose of this investigation was to determine the pharmacokinetic disposition of intravenous

allo-purinol and its metabolite oxypurinol and to

evalu-ate the degree of xanthine oxidase inhibition using serum uric acid as a marker.

Under normal conditions nucleic acids are sequen-tially converted to adenosine, inosine, hypoxanthine, xanthine, and uric acid. Xanthine oxidase in the

pres-ence of oxygen is the enzyme responsible for the

conversion of hypoxanthine to xanthine and

xan-thine to uric acid. However, during periods of

hypoxia-ischemia, the energy-rich nucleotide adeno-sine triphosphate is rapidly catabolized to

hypoxan-thine. Upon a replenished supply of oxygen or

reper-fusion, hypoxanthine and xanthine oxidase form

toxic oxygen free radicals. Although other sources of

toxic-derived free radicals exist, these oxygen free

radicals have been identified as an important medi-ator in the biochemical cascade operative in the pro-duction of cellular injury and tissue necrosis due to ischemia-reperfusion injury.’3 Allopurinol and its metabolite oxypurmnol inhibit xanthine oxidase and this ability may provide a therapeutic intervention to prevent or ameliorate some features of ischemia-reperfusion injury caused by oxygen free radicals.4’#{176}

This study was conducted to aid in the design of

an optimum dosing strategy for a large scale, long-term therapeutic trial to assess allopurinol’s abifity to protect against ischemia-reperfusion injury in neo-nates with congenital heart disease (CHD). The

mod-em conduct of surgical repair of complex CHD is

usually performed under hypothermic total circula-tory arrest. At the completion of the operation,

cir-culation is restored. This clinical practice parallels

the ischemia-reperfusion model of injury with the

exception that circulatory arrest occurs at a body temperature <20#{176}Cand may not result in tissue

injury in the time frame of ischemia.

METHODS

From the *vision of Neurology, The Children’s Hospital of Philadelphia, and the Departments of Neurology and Pediatrics of the University of Pennsylvania School of Medicine; the IDepartment of Pharmacy Practice,

The Philadelphia College of Pharmacy and Science; the §Division of

Car-diology, The Children’s Hospital of Philadelphia, and the Department of Pediatrics of the University of Pennsylvania School of Medicine; and the #Division of Cardiothoracic Surgery, The Children’s Hospital of

Philadel-phia, and the Department of Surgery of the University of Pennsylvania School of Medicine.

Received for publication Sep 29, 1993; accepted Mar 31, 1994.

PEDIATRICS (ISSN 0031 4005). Copyright © 1994 by the American

Acad-emy of Pediatrics.

Study Population

The study population was composed of twelve neonates ad-mitted to the Pediatric Intensive Care Unit or the Infant Intensive

Care Unit at the Children’s Hospital of Philadelphia with an established diagnosis of hypoplastic left heart syndrome requiring

surgery under hypothermic total circulatory arrest between

December 1991 and May 1992. The protocol was approved by the Committee for Protection of Human Subjects Institutional Review

Board. Written informed consent was obtained from a parent of each neonate.

All neonates were studied approximately 36 hours before their

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Serum concentration versus time data were analyzed sepa-rately for each neonate to determine pharmacokinetic parameters of allopurinol using noncompartmental methods.’2 The observed peaks of serum allopurinol, oxypurinol, uric acid, and hypoxan-thine concentrations (C) and corresponding time to reach peak

concentrations (T) were determined by visual inspection of the

0 Allopurinol . Oxypurinol

V Uric Acid

V Hypoxanthine

10

0.1

TABLE 1. Allopurinol Dose and Patient Demographics

Patient Demographics Allopurinol Dose

5 mg/kg 10 mg/kg

(n=6) (n=6) Male/female

Mean postnatal age in days Range

Mean weight in kg

Range

Mean BUN* in mg/dL

Range

Mean creatinine in mg/dL

Range 3/3 2/4 6.2 3-9 3-21 3.0 2.9 2.1-4.1 2.1-4.0 18.7 14.0 8-31 8-25 1.0 0.82 0.6-1.7 0.6-1.4

* BUN, blood urea nitrogen.

0 4 8 12 16

Time (hrs)

*U#{149}jAcid. mg/dl

20 24

Fig 1. TypiCal serum concentration versus time proffle, 5 mg/kg.

ARTICLES 821

scheduled cardiac repair surgery. Neonates were between 3 and

21 days old with weights ranging from 2100 g to 4100 g. All had

normal renal and hepatic function. Six patients received a single, intravenous infusion of 5 mg/kg of allopurinol. The other six

patients received a single allopurinol dose of 10 mg/kg. Patient demographics are provided in Table 1. The groups were similar

(P > .05) with respect to mean postnatal age, body weight, blood

urea nitrogen, and serum creatinine. All of the neonates, with the exception of one in the 10 mg/kg group, were 9 days old.

Drug Administration and Blood Sampling

Sodium allopurinol was the study drug provided (lot #OZ2790

by the Burroughs Wellcome Company, Research Triangle Park,

NC). Each dose was diluted in 5% dextrose to a final concentration of 5 mg/mL and infused over 20 minutes.

Twelve 0.75 mL blood samples were collected via an indwelling

venous or arterial line at the following times: before drug infusion (at time 0), and at times 10 minutes, 20 minutes, I h, 2 h, 3 h, 5 h,

7 h, 9 h, 12 h, 18 h, and 24 h after the start of infusion.

After collection, blood samples were immediately placed on ice

then centrifuged. The serum was separated and stored at -70#{176}C until analysis.

Sample Analysis

Plasma concentrations of allopurinol, oxypurinol, uric acid, and hypoxanthine were measured using a modification of a high

per-formance liquid-chromatography assay procedure by Wung et

al.” All analytic studies were performed at the Philadelphia Col-lege of Pharmacy and Science. Standards for high performance

liquid-chromatography analysis were also provided by The

Bur-roughs Weilcome Company. Samples were thawed and then

deproteinated via ultrafiltration by adding 150 mL of serum to an

Amicon MPS-1 micropartition system (Amicon, Danvers, MA)

which was centrifuged at 2900 rpm for 40 minutes at 25#{176}C.A

50-microliter aliquot of the ultrafiltrate was injected onto a

Beck-man System Gold, Model IIOB (Beckman Instruments, Inc. San Ramon, CA) solvent delivery module using a Model 166

ultravi-olet detector with the absorbance set at 254 nm. Sensitivity of

allopurinol, oxypurinol, and uric acid was 100 ng/mL and 125

ng/mL for hypoxanthine. This assay utilized a5micron,

reversed-phase Ultrasphere (Beckman) C18 250 x 4.6 mm column with a

Direct-Connect (Ailtech, Deerfield, IL) Spherisorb ODS-2 5 micron guard column. The mobile phase consisted of a 99% 0.05 M

potassium phosphate buffer in 1% acetonitrile adjusted to pH 4.6

at a flow rate of I mL/minute. The interday coefficients of

varia-lion of allopurinol, oxypurinol, uric acid, and hypoxanthine were

2.4%, 3.2%, 3.9%, and 1.6%, respectively. Recoveries of each com-pound were >95%. Elution of uric acid, hypoxanthine, oxypurinol,

and allopurinol occurred at approximately 4.6, 6.9, 10.8, and 13

minutes, respectively.

Data Analysis

data. The apparent first-order terminal elimination rate constant

(lc; h’) for allopurinol was calculated by linear regression

analy-sis of the log serum concentration versus time plot for each set of data. The total area under the serum concentration (AUC) versus

time curve from time 0 to infinity (AUC; mg x h/L) and the

area under the first moment curve (AUMC mg x h2/L) were

calculated using the linear trapezoidal rule method. The AUC was extrapolated to infinite time by adding the quotient of the last extrapolated serum concentration and the elimination rate con-stant. Additional pharmacokinetic parameters were calculated us-ing the following formulas: total dearance, (CL; L/h/kg) =

Dose/AUC; mean residence time, (MRT; .h) = AUMC/AUC

+ infusion tiine/2; and the calculated steady state volume of

distribution, (V L/kg) = (Dose x AUMC)/AUC - (Dose x infusion time)/(2 x AUC). Differences between pharmacokinetic

parameters of each group were compared using the

Mann-Whitney LI test. Linear associations between allopurinol and

oxypurinol pharmacokinetic parameters and degree of uric acid reduction as well as increase in serum hypoxanthine

concen-trations were examined using calculated Pearson correlation

coefficients. The a priori significance level for all comparisons

was

P

< .05. Data was analyzed using the SPSS/PC+ computer software package.

RESULTS

Figures 1 and 2 demonstrate typical plots that

depict changes in serum allopurinol, oxypurinol, uric

acid, and hypoxanthine concentrations for neonates

receiving 5-mg/kg and 10-mg/kg, respectively. The

mean serum allopurinol concentration versus time

profile is depicted in Figure 3. Mean

pharmacoki-netic parameters following single intravenous doses

of allopurinol at 5 mg/kg and 10 mg/kg are

sum-marized in Table 2. There are no statistically

signifi-cant differences in pharmacokinetic parameters

between the 5-mg/kg and 10-mg/kg groups.

Allo-purinol is rapidly eliminated from the body as sug-gested by a mean allopurinoi plasma half-life (t#{189})of approximately 2.5 hours.

The mean serum oxypurinol concentration versus

time proffle is shown in Figure 4. Serum oxypurinol

C, and T are summarized in Table 3.

Oxypuri-nol C appears to be dose-related.

The effect of the 5-mg/kg and 10-mg/kg doses of

allopurinol on serum uric acid concentrations is

shown in Table 4. The time to uric acid nadir is

0 (0 ..-) Q) 0 0 0

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(3)

10

0 Allopurinol

. Oxypurinol

V Uric Acid

V Hypoxanthine E C 0 a C C 1) C 0 0 01

. 5 mg/kg

=. 10 0 10 mg/kg

as C 0 a I. C a) 0 C 0 C) 0.1 0 25

Fig 4. Mean serum oxypurinol concentration versus time.

0 4 8 12 16 20 24

‘Uric Acid, mg,’dl

Time (hrs)

5 10 15 20

Time (hours)

. 5 mg/kg

0 10 mg/kg

0 5 10

Time (hours)

. 5 mg/kg

0 10 mg/kg

Time (hours) Fig 2. Typical serum concentration versus time profile, 10 mg/kg.

E a) C 0 0 C a 0 C 0 C) 100 10 0.1

Fig 3. Mean serum allopurinol concentration versus time.

15

TABLE 2. Allo purinol Pharmaco kinetic Data

Parameter 5 mg/kg 10 mg/kg

P

Value Mean ± SD (n = 6) (n = 6)

K: (h-’) 0.317 ± 0.225 0.360 ± 0.159 NS

C01(L/h/kg) 0.608 ± 0.567 0.310 ± 0.148 NS

VJL/kg) 1.646 ± 1.095 0.815 ±0.267 NS

MRT (h) 3.77 ±2.74 2.77 ± 0.55 NS

* Abbreviations: K, first-order terminal elimination rate constant; CLoiai, total clearance; VI, steady state volume of distribution;

MRT, mean residence time; NS, not significant.

similar in both groups and occurs at approximately

16 hours. The reduction in mean serum uric acid

level was greater in those who received a 10-mg/kg dose of allopurinol, but the difference was not sta-tistically significant. The mean initial uric acid level was 3.69 mg/dL ± 2.06 mg/dl (SD) and significantly

fell to a mean nadir value of 2.125 mg/dL ± 1.29

mg/dL (SD) after allopurinol administration

TABLE 3. Serum Oxypurinol Results

Parameter 5 mg/kg 10 mg/kg

P

Value

Mean ± SD (n = 6) (n = 6)

Cm): (mg/mL) 6.08 ± 5.82 11.92 ± 2.07 NS

T (h) 7.28 ±5.97 11.63 ± 5.02 NS

* Abbreviations: C maximum serum concentration; T time

to maximum serum concentration; NS, not significant.

TABLE 4. Serum Un c Acid (UA) Results

Parameter

Mean ± SD

5 mg/kg

(n = 6)

10 mg/kg

(n =6)

P

Value

Baseline UA (mg/dL) UA nadir (mg/dL) Time to nadir (h)

Max UA reduction (%)

3.65 ±2.60 2.15 ±1.62 15.83 ± 9.35

39.99 ±14.39

3.73 ±1.02 2.10 ± 0.68 15.63 ±5.91 43.94 ± 11.88

NS NS NS NS 0 0) E C 0 0 C a 0 C 0 I.) 6 4, 2 0

-5 0 5 10 15 20 25

Fig 5. Mean serum uric acid concentration versus time.

(P = .0001). A mean uric acid concentration versus

time plot is shown in Figure 5. DISCUSSION

The medical approach to the treatment of the

(4)

ARTICLES 823

circulation to the whole body and prevent

hypoxic-ischemic injury until palliative or corrective surgery restores a more normal circulatory physiology.

Surgery in the neonate with some forms of CHD,

particularly the hypoplastic left heart syndrome, re-quires a period of hypothermic total circulatory ar-rest. The sharp reduction in metabolic demands

in-duced by the hypothermia preserves much of the

cellular integrity during total circulatory arrest. At the completion of surgical repair circulation is re-stored. It is at this time of reperfusion that production of free radicals can occur when oxygen is converted by newly activated xanthine oxidase in the presence of hypoxanthine to toxic species of free radicals.

We have hypothesized that cell injury by such a mechanism may be reduced by preoperative admin-istration of allopurinol and its metabolite oxypurinol via xanthine oxidase inhibition, the enzyme cata-lyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid. Uric acid reduction reflects xanthine oxidase inhibition.

This pharmacokinetic pilot study reveals allopuri-nol’s ability to inhibit xanthine oxidase, as measured by a prompt and significant reduction in serum uric acid by about 40% from baseline. Our data also show that there are no statistically significant differences in the

values of measured pharmacokinetic parameters or

percent uric acid reduction between a 5-mg/kg dose

and a 10-mg/kg dose of intravenous allopurinoL

Therapeutic strategies such as preoperative

ad-ministration of allopurinol are intended to augment

the neuroprotective benefits of deep hypothermia and inhibit or prevent cell injury at the time of reper-fusion after ischemia. This may reduce the threat of brain or multiorgan damage and preserve the long-term neurologic integrity of survivors.

We are now conducting a long-term, blinded,

ran-domized controlled treatment trial to determine

whether preoperative administration of allopurmnol

reduces the risk of death or brain, myocardial, or

other organ damage in neonates with CHD requiring

hypothermic total circulatory arrest.

ACKNOWLEDGMENT

This work was supported by NIH Contract NO1-NS-1-2315

(Ors Clancy, McGaurn, and Murphy).

REFERENCES

1. McCord JM. Oxygen-derived free radicals in post-ischemic tissue

injury.

N

Engi JMed. 1985312:159-163

2. Paft A, Harken AM, Burton LK, et al. Xanthine o,ddase-derived

hydro-gen pemxide contributes to ischemia reperfusion-induced edema in

gerbil brains. IClin Invest. 198881:1556-1562

3. Chambers DE, Parks DA, Patterson G, et al. Xanthine oxidase as a source of free radical damage in myocardial ischemia. IMo! Ce!! Cardiol.

1985;17:145-152

4. Cmwell JW, Jones CE, Smith EE. Effect of allopurinol on hemorrhagic

shock. Am IPhysiol. 1969216:744-748

5. Martz D, Rayos G, Schielke GP, Betz AL Allopurinol and

dimethyl-thiourea reduce brain infarction following middle cerebral artery ocdusion in rats Stroke. 198920:488-494

6. Itoh T, Kawakasni M, Yamauchi Y, Shimizu 5, Nakamura M. Effect of

allopurinol on ischemia and reperfusion-induced cerebral injury in

spontaneously hypertensive rats. Stroke. 1986;17:1284-1287

7.

lansek R, Packham D, Aspey BS, Harrison MJ. An assessment of the

possible protective effect of allopurinol in acute stroke. J Neurol

Neurosurg Psychiatry. 1966;49:585-587

8. Toledo-Pereyra LH, Simmons RL, Najarian JS. Effect of allopurinol on the preservation of ischemic kidneys perfused with plasma or plasma

substitutes. Ann Surg. 1974;180:780-782

9. Palmer C, Vannucci RC, Towfighi J,DuPlessis AJ, Vickers F. Ailopuri-nol reduces hypoxic-ischemic (HI) brain injury. Pediatr Res. 1989;25:

359A

10. Soda D, Nemeth I, Henez P, Denes K. Effect of allopurinol treatment in

premature infants with idiopathic respiratory distress syndrome. Dev

Pharinacol Ther. 1984;7:357-367

11. Wung WE, Howell SB. Simultaneous liquid chromatography of

5-flur-ouracil, uridine, hypoxanthine, xanthine, allopurinol, and oxypurinol in

plasma. Clin Chem. 198026:1704-1708

12. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel

Dekker, Inc; 1982:409-417

A PLEA FOR SIMPLICITY AND LARGE SAMPLE SIZE

“Most [clinical] trials would be of much greater scientific value if they collected

ten times less data, both at entry and during follow-up, and were therefore much

larger.

Peto R, Coffins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials. In: Warren KS, Mosteller F, eds. Doing More Good Than Harm: The Evaluation of Health Care Interventions.”

Ann NY Acad Sci. 1993;703:314-340.

Submitted by Student

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1994;94;820

Pediatrics

Murphy, Marshall L. Jacobs and William I. Norwood

Susan Phillips McGaurn, Robert R. Clancy, Lisa E. Davis, Motria M. Krawczeniuk, John D.

Left Heart Syndrome

The Pharmacokinetics of Injectable Allopurinol in Newborns With the Hypoplastic

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1994;94;820

Pediatrics

Murphy, Marshall L. Jacobs and William I. Norwood

Susan Phillips McGaurn, Robert R. Clancy, Lisa E. Davis, Motria M. Krawczeniuk, John D.

Left Heart Syndrome

The Pharmacokinetics of Injectable Allopurinol in Newborns With the Hypoplastic

http://pediatrics.aappublications.org/content/94/6/820

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1994 by the

been published continuously since 1948. Pediatrics is owned, published, and trademarked by the

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has

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