Spinal Cord Bioavailability of Methylprednisolone After
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156 Anesthesiology 2000; 92:156–63 © 2000 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Spinal Cord Bioavailability of Methylprednisolone after Intravenous and Intrathecal Administration The Role of P-Glycoprotein Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/92/1/156/398816/0000542-200001000-00027.pdf by guest on 30 September 2021 Kari L. Koszdin, D.V.M.,* Danny D. Shen, Ph.D.,† Christopher M. Bernards, M.D.‡ Background: High-dose intravenously administered methyl- cord bioavailability of methylprednisolone is poor after intra- prednisolone has been shown to improve outcome after spinal venous administration. The studies in knockout mice suggest cord injury. The resultant glucocorticoid-induced immunosup- that this poor bioavailability results from P-glycoprotein–medi- pression, however, results in multiple complications including ated exclusion of methylprednisolone from the spinal cord. sepsis, pneumonia, and wound infection. These complications (Key words: Friend leukemia virus strain B; mdr 1a/1b (2/2); could be reduced by techniques that increase the spinal bio- mice.) availability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This HIGH-dose methylprednisolone has been shown to be an study aimed to characterize the spinal and plasma bioavailabil- ity of methylprednisolone after intravenous and intrathecal effective treatment for acute spinal cord injury. The administration and to identify barriers to the distribution of Third National Acute Spinal Cord Injury Study demon- methylprednisolone from plasma into spinal cord. strated that patients receiving an intensive 24- to 48-h Methods: The spinal and plasma pharmacokinetics of intra- 21 21 intravenous methylprednisolone regimen (30-mg/kg bo- venous (30-mg/kg bolus dose plus 5.4 mg z kg z h ) and 21 21 2 2 lus dose plus 5.4 mg z kg z h ) within8hoftheinjury intrathecal (1-mg/kg bolus dose plus 1 mg z kg 1 z h 1) methyl- prednisolone infusions were compared in pigs. In addition, had improved 6-month recovery compared with place- 1 wild-type mice and P-glycoprotein knockout mice were used to bo-treated patients. This “megadose” steroid therapy determine the role of P-glycoprotein in limiting spinal bioavail- was not without adverse effects, however. Patients in ability of methylprednisolone. the methylprednisolone treatment groups experienced a Results: Despite the greater intravenous dose, concentrations 2.6-fold increase in the incidence of severe pneumonia of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal adminis- and sepsis, an increased incidence of wound infection, tration. After intraperitoneal administration in the mouse, the an increased number of days spent receiving mechanical concentrations of methylprednisolone in muscle were not dif- ventilation, and an increased number of days spent in the ferent between mice expressing P-glycoprotein (2.39 6 1.79 intensive care unit.1–4 These complications are believed m 6 m g/g) and those lacking P-glycoprotein (2.83 0.46 g/g). In to result from glucocorticoid-induced immune suppres- contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of sion. P-glycoprotein–deficient mice were similar to those in skeletal In addition to these documented complications, there muscle (2.83 6 0.27 mg/g). are also valid theoretical concerns associated with high- Conclusions: These pig studies demonstrate that the spinal dose glucocorticoid therapy in the setting of neural in- jury. These include steroid-induced hyperglycemia and * Senior Fellow, Department of Comparative Medicine. sepsis-related hypotension, both of which may contrib- 5,6 † Professor, Department of Pharmaceutics. ute to secondary neuronal injury. This may explain ‡ Associate Professor, Department of Anesthesiology. why some studies investigating use of high-dose steroids Received from the Departments of Comparative Medicine, Pharma- for spinal cord injury have failed to demonstrate a ben- 7,8 ceutics, and Anesthesiology, University of Washington, Seattle, Wash- efit. ington. Submitted for publication April 15, 1999. Accepted for publi- One approach to improving methylprednisolone ther- cation July 22, 1999. Supported in part by grants no. RO1 NIDA apy in acute spinal cord injury would be to increase the RR07019-06 and RO1 NS 38911-01 from the National Institutes of Health, Bethesda, Maryland. fraction of the steroid dose reaching the spinal cord while minimizing systemic drug exposure. This goal Address reprint requests to Dr. Bernards: Department of Anesthesi- ology, University of Washington, Box 356540, Seattle, Washington could be accomplished by administering methylpred- 98195. Address electronic mail to: [email protected] nisolone directly at the site of injury or by developing Anesthesiology, V 92, No 1, Jan 2000 157 SPINAL BIOAVAILABILITY OF METHYLPREDNISOLONE strategies to increase spinal cord drug exposure after 0.8% and 2.0%. The left femoral vein was cannulated for intravenous administration of methylprednisolone. infusion of either methylprednisolone or 0.9% saline (70 This study therefore was designed to characterize the ml/h) containing pancuronium bromide (0.04 mg/ml). spinal cord and plasma bioavailability of methylpred- Pancuronium bromide was used to ensure that the ani- nisolone after intravenous and intrathecal administra- mal would not move during and after placement of the tion. This was accomplished using a pig microdialysis microdialysis probe. When methylprednisolone was ad- model to characterize the spinal cord, cerebrospinal ministered intravenously, the saline/pancuronium solu- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/92/1/156/398816/0000542-200001000-00027.pdf by guest on 30 September 2021 fluid (CSF), and plasma pharmacokinetics of methylpred- tion was administered into an ear vein. Rectal tempera- nisolone during intravenous and intrathecal administra- ture was maintained at 38°C using a servo controlled tion. heat lamp and a rectal temperature probe (YSI model An additional goal was to identify potential barriers to 73A; Yellow Springs Instrument Co., Yellow Springs, the spinal cord bioavailability of methylprednisolone af- OH). ter intravenous administration. One potential barrier is Manufacture of Microdialysis Probes. Two types of P-glycoprotein (mdr1 gene product),9 an efflux trans- microdialysis probes were used to sample concentra- porter for which methylprednisolone has been identified tions of methylprednisolone in this study: linear probes, recently as a substrate. This membrane-bound protein which were inserted into the spinal cord, and loop has been shown to limit the cellular accumulation of probes, which were inserted into the subarachnoid many drugs and is expressed in spinal cord capillary space. Both types of probes were prepared from cellu- endothelium.10 Thus, we hypothesized that the poor lose microdialysis fibers (Spectrum Medical Industries, bioavailability of methylprednisolone after intravenous Houston, TX) with a 215-mm ID, a 235-mm OD, and a administration results from active exclusion of the drug molecular weight cutoff of 6,000 D. India ink was used from the spinal cord by P-glycoprotein. To address this to paint calibration marks on the dialysis probes to de- question, we used a transgenic mouse model that lacks fine a “dialysis window.” For the linear probes, the dial- two key P-glycoprotein genes (mdr 1a and mdr 1b)to ysis window was 2 mm long; for the loop probes, the determine the role of this transporter in limiting the dialysis window was 20 mm long. Epoxy cement was spinal cord bioavailability of methylprednisolone after spread evenly over the probes on either side of the systemic administration. dialysis windows by running a 1-cm length of polyethyl- ene 10 tubing along the dialysis fiber. The polyethylene 10 tubing had an ID of 280 mm; thus, the finished dialysis Methods probes had an OD of 280 mm. A 90-mm diameter wire was inserted into the lumen of All experiments were performed in accordance with a the loop dialysis probe, and the probe was bent at the protocol approved by the Animal Care and Use Commit- center of the dialysis window to form a dialysis loop. The tee at the University of Washington. American Associa- wire ensured that the probe remained patent after being tion for Laboratory Animal Care guidelines were fol- bent. A conical bead of silicone caulk was then placed lowed throughout. along the neck of the probe. For intrathecal administra- tion of methylprednisolone, an intrathecal catheter (Bec- Pig Microdialysis ton Dickinson and Co., Franklin Lakes, NJ) was secured Animals. Mixed-breed pigs (n 5 20) of both sexes, to the neck of the lumbar loop probe with silicone caulk. weighing 10–15 kg, were used. Each animal was anes- The probes were allowed to cure for $24 h but ,72 h thetized via face mask with halothane and nitrous oxide before insertion. (70%) in oxygen. After intramuscular injection of succi- In Vitro Calibration of Probes. Four loop probes nylcholine (100–200 mg), the pigs were intubated oro- and four linear probes, which had not been implanted in tracheally and ventilated mechanically. Minute ventila- animals, were placed in a solution of methylpred- 6 m tion was adjusted to maintain end-tidal CO2 at 40 3 nisolone (5 g/ml) and perfused with mock CSF for 1 h mmHg. at 10 ml/min. Samples were collected at 10-min intervals