Pharmacokinetic profile of epidurally administered methylnaltrexone, a novel peripheral opioid antagonist in a rabbit model

D. B. Murphy*,1, H. El Behiery1, V. W. Chan1 and J. F. Foss2

1Department of Anaesthesia, The Toronto Western Hospital and University of Toronto, Toronto, Ontario, Canada. 2Department of Anaesthesia and Critical Care, University of Chicago, Chicago IL, USA*Corresponding author: Department of Anaesthesia, Intensive Care and Pain Management,Cork University Hospital, Wilton, Cork City, Ireland

Accepted for publication: August 15, 2000


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Methylnaltrexone (MNTX) is the first peripheral opioid receptor antagonist used in man to treat acute and chronic opiate-mediated side-effects. We describe in a rabbit model the pharmacokinetics of epidurally administered MNTX 0.66 mg kg–1, and we tested the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space. There were minimal concentrations of MNTX (40 ng ml–1) detected in the CSF at 10 and 20 min and none thereafter in comparison with the high serum levels. The serum drug concentration–time profile fitted a two-compartment pharmacokinetic model. Further studies are warranted as epidurally administered MNTX may have the potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.

Br J Anaesth 2001; 86: 120–2

Keywords: anaesthetic techniques, epidural; pharmacokinetics, methylnaltrexone; rabbit


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Epidural opioid compounds are used for analgesia in clinical practice in patients suffering from acute and chronic pain. Common peripheral undesirable side-effects of epidural opioids include urinary retention, constipation and delayed gastric emptying, but the exact mechanisms remain unclear.1 Epidural opioids may mediate these side-effects via a central, spinal and/or direct effect on local opioid receptors.1 The relative contributions of each mechanism are unknown.

Methylnaltrexone (MNTX) is a quaternary opioid antagonist with limited ability to cross the blood–brain barrier. In man, intravenous MNTX has been shown to reverse morphine-induced delayed gastric emptying2 and to reverse constipation due to chronic methadone use3 without affecting centrally mediated analgesia. We postulated that if MNTX does not cross the dura it might have potential to reverse peripherally mediated side-effects of epidural opioids without affecting analgesia. Therefore, the purpose of this study was to describe the pharmacokinetics of epidurally administered MNTX and to test the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space (SAS).


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
With approval of the Animal Care and Research Committee of the University of Toronto, seven rabbits (3.3–3.5 kg) were anaesthetized with isoflurane in nitrous oxide and oxygen. A 22 g cannula was inserted in an ear vein and artery for blood sample collection and blood gas measurement. The trachea was intubated with a 4 mm (internal diameter) endotracheal tube and pancuronium 0.3 mg kg–1 was administered to produce muscle relaxation. The animals were placed prone on the operating table and the head was fixed in a modified stereotactic frame. The rabbits’ lungs were ventilated (Harvard animal ventilator) to normocapnia and 10 ml kg–1 normal saline was administered every 30 min. The L3 or L4 vertebra was exposed via a midline lumbar incision by retracting the paraspinal muscles laterally. After laminectomy of one of the vertebra, a 22 g catheter was placed in the epidural space under direct vision. The cannula was inspected for the presence of CSF and aspirated. If CSF was detected the animal was discarded and replaced. After confirmation of placement in the epidural space the catheter was fixed in place with dental cement.

A midline skin incision was made over the shaved back of the neck covering the occipital bone and cervical dorsum. The atlanto-occipital membrane was identified and a 22 g cannula was inserted in the base of the skull covering the cisterna magna, cephalad to the occipital–atlas junction. Spontaneous CSF flow was obtained and allowed to drain freely. The cannula was immobilized with dental cement. MNTX 0.66 mg kg–1 (Mallinckrodt Specialty Chemicals, St Louis, MO, USA) was administered in 1ml of normal saline via the epidural catheter and blood and CSF samples were taken 0, 3, 6, 10, 15, 20, 40, 60, 120 and 180 min after drug administration. The epidural dose of MNTX was chosen on the basis of previous results,2 3 with the aim of administering a relatively high dose of MNTX. Animals were euthanized after 3 h by pentobarbital overdose. Blood samples were centrifuged, separated immediately and the serum and CSF sample was frozen at –80°C for later analysis by high-performance liquid chromatography. Using the modified procedure from the method of Kim et al.,4 standard curves of MNTX were run for each set of samples. The lower limit of detection was 2 ng ml–1. Pharmacokinetic parameters for MNTX were calculated using WinNonlinTM (2.1 Scientific Consulting, Mountain View, CA, USA).

Seven rabbits were enrolled in the study, but data from two were excluded due to difficulty in CSF or blood sampling techniques. Results are expressed as mean (SD) unless stated otherwise. The mean weight of the animals was 3.5 (0.3) kg. The serum drug concentration –time profile for each animal fitted a biexpontential function. Therefore, the disposition of epidural MNTX could be described by a two-compartment model in which the drug is eliminated from the central compartment. The mean serum and CSF MNTX concentrations determined during the duration of the study are shown in Fig. 1. There were minimal amounts of MNTX detected in the CSF at up to 20 min and none thereafter. The following pharmacokinetic data were calculated: area under the curve [AUC0–240 11920 (3892) ng min–1 ml–1], peak concentration [Cmax 215 (35) ng–1 ml–1], time to maximum concentration (Tmax 10 min), total volume of distribution [Vz 5199 (1199) ml kg–1], total body clearance [CL 86 (26) ml min–1 kg–1] and ß half-life [T1/2 ß 74.96 (35) min–1]



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Fig 1 Plot of serum and CSF concentrations of methylnaltrexone (ng ml–1) after epidural administration of methylnaltrexone 0.66 mg kg–1. Data are mean (SD). *P<0.05, CSF vs serum (Mann–Whitney U-test).

 

    Comment
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
This is the first study to describe the pharmacokinetics of epidurally administered MNTX. After epidural administration, minimal concentrations of the drug were detected in the CSF compared with plasma. Previous studies in animals and man showed the ratio of peak CSF:serum morphine levels are of the order of 35:1 after epidural morphine administration.5 However, in this study the CSF:serum ratio was reversed to 1:5 after high-dose epidural MNTX, suggesting that high doses of epidural MNTX do not appear to cross the dural membrane significantly and would not have clinical implications. Its relative lack of dural penetration may be due to the presence of a bulky quaternary charged N2 atom in the drug molecule. The low concentration of MNTX seen in the CNS was produced by the administration of doses very much larger than those expected to be used clinically. MNTX has significantly lower affinity for the opioid receptor than naltrexone6 and the maximum concentration detected in the CSF is unlikely to have clinical implications. However, evaluation of this low CNS penetration would need to be studied in the clinical setting. Therefore, we postulate that, during coadministration of centrally acting opioids and MNTX in the epidural space, MNTX absorbed into the vascular compartment will act only on peripheral opioid receptor while maintaining centrally mediated analgesia.

After epidural administration of MNTX 0.66 mg kg–1, peak serum values were greater than 200 ng ml–1. These systemic drug levels may possibly be of therapeutic significance. In patients on chronic opioid therapy who received i.v. MNTX in doses up to 0.35 mg kg –1 over 1 min, rapid laxation was induced without evidence of withdrawal or diminished analgesia. Peak plasma levels of 162 (237) ng ml –1 were observed without side-effects in that group.3

In conclusion, epidurally administered MNTX does not appear to gain significant access to the CSF. Further studies are warranted as epidurally administered MNTX may have potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.


    Acknowledgements
 
The authors wish to acknowledge the support of the Canadian Anesthesiologists’ Society Award to H. El Behiery.


    References
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995; 42: 891–903[Abstract]

2 Murphy DB, Sutton JA, Prescott LF, et al. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997; 87: 765–70[ISI][Medline]

3 Yuan CS, Foss JF, O’Connor M et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. J Am Med Assoc 2000; 283: 367–72[Abstract/Free Full Text]

4 Kim C, Cheng R, Corrigall WA, et al. Assay for methylnaltrexone in rat brain region by serum high performance liquid chromatography with colorimetric electrochemical detection. Chromatographia 1989; 28: 359–63[ISI]

5 Brose WG, Tanelian DL, Brodsky JB, et al. CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration. Pain 1991; 45: 11–5[ISI][Medline]

6 Brown DR, Goldberg LI. The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 1985; 24: 181–91[ISI][Medline]