Does Secretory Clearance Follow Glomerular Filtration Rate in Chronic Kidney Diseases? Reconsidering the Intact Nephron Hypothesis.

Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs.

Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

Use of glucosamine and chondroitin supplements and risk of colorectal cancer.

PURPOSE: Glucosamine and chondroitin are non-vitamin, non-mineral supplements which have anti-inflammatory properties. These supplements are typically used for joint pain and osteoarthritis and are commonly taken as either glucosamine alone or glucosamine plus chondroitin. An exploratory analysis conducted within the VITamins And Lifestyle (VITAL) study observed any use of glucosamine and chondroitin to be associated with reduced risk of colorectal cancer (CRC) after 5 years of follow-up. METHODS: With two additional years of follow-up, we have studied these associations in greater depth, including associations by frequency/duration of use and by formulation, and have evaluated whether observed associations are modified by factors associated with inflammation. Participants include 75,137 western Washington residents aged 50-76 who completed the mailed VITAL questionnaire between 2000 and 2002. Use of glucosamine and chondroitin was ascertained by questions about supplement use during the 10-year period prior to baseline, and participants were followed for CRC through 2008 (n = 557). Cox regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: Persons reporting use of glucosamine + chondroitin on 4+ days/week for 3+ years had a non-statistically significant 45 % lower CRC risk than non-users (HR: 0.55; 95 % CI 0.30-1.01; p-trend: 0.16). This association varied by body mass index (p-interaction: 0.006), with inverse association observed among the overweight/obese (p-trend: 0.02), but not among the underweight/normal weight. Use of glucosamine alone was not significantly associated with CRC risk. CONCLUSIONS: There is great need to identify safe and effective cancer preventive strategies, suggesting that glucosamine and chondroitin may merit further attention as a potential chemopreventive agent.

Measurement and compartmental modeling of the effect of CYP3A5 gene variation on systemic and intrarenal tacrolimus disposition.

We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype. As compared with CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent area under the curve (AUC) ratios for 31-desmethyl tacrolimus (31-DMT), 12-hydroxy tacrolimus, and 13-desmethyl tacrolimus (13-DMT). In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors as compared with nonexpressors. To explore the mechanism behind this observation, we developed a semiphysiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that, at steady state, intrarenal accumulation of tacrolimus and its primary metabolites will depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient differences in the risk of tacrolimus-induced nephrotoxicity.

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype.

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.

Clonidine pharmacokinetics in pregnancy.

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

Semi-quantitative RT-PCR method to estimate full-length mRNA levels of the multidrug resistance gene.

Expression levels of P-glycoprotein (P-gp), the transporter encoded by the human multidrug resistance gene (MDR1), may play an important role in drug disposition. The ability to quantitate full-length MDR1 mRNA levels may be predictive of P-gp expression and function. Therefore, a semi-quantitative RT-PCR assay was developed to assess full-length MDR1 mRNA levels. Levels offull-length 3.8-kb MDR1 mRNA were estimated by comparing PCR amplification of the RNA extract with that of an internal standard, deltaMDR1. The 2.9-kb deltaMDR1 competitor RNA standard was constructed by deleting 965 bpfrom the interior of MDR1 mRNA. The full-length MDR1 and deltaMDR1 share identical 5' and 3'primer binding sequences, allowing for their simultaneous amplification in the same RT-PCR. With this approach, MDR1 mRNA levels can be sensitively and reliably estimated with a detection limit of 2000 copies. Full-length MDR1 mRNA levels in various human cell lines and lymphocytes from leukemia patients varied over 100-fold, ranging from 0.3 to 36.5 x 10(5) copies/microg total RNA. The semi-quantitative full-length RT-PCR assay may be useful in estimating MDR1 mRNA levels to assess P-gp expression, which may be important in studying the role of P-gp in drug disposition and cancer chemotherapy efficacy.

Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients.

PURPOSE: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment. METHODS: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations. RESULTS: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy CONCLUSIONS: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.

In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration.

We investigated whether a single plasma midazolam concentration could serve as an accurate predictor of total midazolam clearance, an established in-vivo probe measure of cytochrome P450 3A (CYP3A) activity. In a retrospective analysis of data from 224 healthy volunteers, non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time curves following intravenous (IV) and/or oral administration. Based on statistical moment theory, the concentration at the mean residence time (MRT) should be the best predictor of the total area under the curve (AUC). Following IV or oral midazolam administration, the average MRT was found to be approximately 3.5 h, suggesting that the optimal single sampling time to predict AUC was between 3 and 4 h. Since a 4-h data point was common to all studies incorporated into this analysis, we selected this time point for further investigation. The concentrations of midazolam measured 4 h after an IV or oral dose explained 80 and 91% of the constitutive interindividual variability in midazolam AUC, respectively. The 4-h midazolam measurement was also an excellent predictor of drug-drug interactions involving CYP3A induction and inhibition. Compared with baseline values, the direction and magnitude of change in midazolam AUC and the 4-h concentration were completely concordant for all study subjects. We conclude that a single 4-h midazolam concentration following IV or oral administration represents an accurate marker of CYP3A phenotype under constitutive and modified states. Moreover, the single-point approach offers an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.

The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo.

UNLABELLED: Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-alpha-dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo. IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.

Can oral midazolam predict oral cyclosporine disposition?

Effective cyclosporine therapy is confounded by large interindividual differences in oral bioavailability and a narrow therapeutic window. Because cytochrome P450 (CYP) 3A-mediated first-pass metabolism contributes to this unpredictable bioavailability, an in vivo oral CYP3A phenotyping probe could be a valuable tool in optimizing cyclosporine therapy. Based on similarities in the metabolic kinetics of cyclosporine and midazolam by the liver and intestinal mucosa, we evaluated whether midazolam oral clearance would predict cyclosporine oral clearance when the two drugs were administered to 20 medically stable kidney transplant recipients. Despite earlier findings in liver transplant recipients who displayed a strong correlation between the systemic clearances of midazolam and cyclosporine, there was a weak correlation between their oral clearances in the current group of subjects (r(s)=0.50, P=0.03). Differing extents of intestinal first-pass metabolic extraction between the two drugs, inhibition of midazolam metabolism by cyclosporine at the level of the intestine, and/or P-glycoprotein-mediated intestinal efflux of cyclosporine (but not midazolam) may account for this poor correlation. We conclude that although oral midazolam is unlikely to be clinically useful as a probe for cyclosporine disposition, its utility in the prediction of other orally administered CYP3A substrates cannot be out ruled.

Morphine-fluoxetine interactions in healthy volunteers: analgesia and side effects.

The authors evaluated the ability of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), to enhance the analgesic potency of morphine. Fifteen volunteers participated in this double-blind crossover study. All received combinations of morphine or saline with either fluoxetine 30 mg or placebo. The authors used individual morphine pharmacokinetics to program an infusion pump to achieve plasma morphine levels of 15, 30, and 60 ng/ml. Analgesia during morphine infusion was assessed using a model of electrical tooth stimulation. Subjective side effects, measurements of end-tidal CO2, O2 saturation, pupil size, and testing of psychomotor performance were obtained. Plasma morphine concentrations were not affected by fluoxetine. In comparison to placebo, oral fluoxetine resulted in less sedation during morphine infusion and less nausea during morphine washout. Morphine-induced pruritus, psychomotor function, and respiratory depression were unaffected by fluoxetine. Acute administration of 30 mg oral fluoxetine augmented analgesia by approximately 3% to 8% and reduced morphine-associated nausea, mood reduction, and drowsiness.

Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study.

Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a low brain-to-unbound plasma concentration ratio (< or =0.5) at steady state. Previous pharmacokinetic studies suggested that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-brain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measure drug concentration in the brain extracellular fluid (ECF) of the cerebral cortex during steady-state i.v. infusion with VPA alone or with VPA plus probenecid. Probenecid co-infusion elevated VPA concentration in the brain tissue surrounding the tip of the microdialysis probe to a greater extent than in the ECF (230% versus 47%). Brain intracellular compartment (ICC) concentration was estimated. In control rabbits, the ICC concentration was 2.8+/-0.28 times higher than the ECF concentration. Probenecid co-infusion elevated the ICC-to-ECF concentration ratio to 4.2+/-0.44, which confirms the existence of an efflux transport system in brain parenchymal cells. The ECF-to-unbound plasma concentration ratio was well below unity (0.029), indicating an uphill efflux transport of VPA across the BBB. Co-infusion of probenecid did not have a significant effect on VPA efflux at the BBB as evidenced by a minimal change in the ECF-to-unbound plasma concentration ratio. This study suggests the presence of distinctly different organic anion transporters for the efflux of VPA at the parenchymal cells and capillary endothelium in the brain.

The effects of intrathecal morphine encapsulated in L- and D-dipalmitoylphosphatidyl choline liposomes on acute nociception in rats.

UNLABELLED: Liposomes can serve as a sustained-release carrier system, permitting the spinal delivery of large opioid doses restricting the dose for acute systemic uptake. We evaluated the antinociceptive effects of morphine encapsulated in liposomes of two isomeric phospholipids, L-dipalmitoylphosphatidyl choline (L-DPPC) and D-dipalmitoylphosphatidyl choline (D-DPPC), in comparison with morphine in saline. Sprague-Dawley rats with chronic lumbar intrathecal catheters were tested for their acute nociceptive response using a hindpaw thermal escape test. Their general behavior, motor function, pinna reflex, and corneal reflex were also examined. The duration of antinociception was longer in both liposomal morphine groups than in the free morphine group. The peak antinociceptive effects were observed within 30 min after intrathecal morphine, L-DPPC or D-DPPC morphine injection. The rank order of the area under the effect-time curve for antinociception was L-DPPC morphine > D-DPPC morphine > morphine. The 50% effective dose was: 2.7 microg (morphine), 4.6 microg (L-DPPC morphine), and 6.4 microg (D-DPPC morphine). D-DPPC morphine had less side effects for a given antinociceptive AUC than morphine. In conclusion, L-DPPC and D-DPPC liposome encapsulation of morphine prolonged the antinociceptive effect on acute thermal stimulation and could decrease side effects, compared with morphine alone. IMPLICATIONS: Two isomers of liposome (L-dipalmitoylphosphatidyl choline and D-dipalmitoylphosphatidyl choline) encapsulation of morphine prolonged the analgesic effect on acute thermal-induced pain when administered intrathecally and could decrease side effects, compared with morphine alone.

Analysis of hydroxylated and N-dealkylated metabolites of terfenadine in microsomal incubates by liquid chromatography--mass spectrometry.

This report describes an assay for the H(1)-receptor antagonist, terfenadine, and its two primary metabolites, terfenadine alcohol (TOH) and azacyclonol (AZ), using positive-ion, electrospray ionization-liquid chromatography-mass spectrometry. The assay was developed in support of kinetic studies of terfenadine oxidative metabolism in human liver and intestinal microsomes, which required quantification of incubate metabolites at low nanomolar concentrations. Terfenadine metabolites were extracted from basified microsomal incubates into methylene chloride. Reconstituted extracts were subject to liquid chromatographic separation on a cyano-reverse phase column. The [M+H]+ ions of terfenadine, terfenadine metabolites, and internal standard were monitored in the effluent by quadrupole mass spectrometry. The assay demonstrated linearity over an incubate concentration range of 5-250 and 12.5-1250 ng/ml for the metabolites and the parent drug, respectively. The respective limits of detection and quantitation for all three analytes were 1.5 and 5 ng/ml of microsomal incubate. Replicate analysis of quality control samples exhibited intra-day coefficients of variation ranging from 3.3% to 7.8% for the three analytes. The corresponding inter-day coefficients of variation ranged from 4.2% to 8.6%. The reproducibility and sensitivity of the assay, combined with the selectivity of mass spectrometric detection, should allow an accurate kinetic characterization of terfenadine oxidation mediated by the high affinity CYP3A enzymes in human liver and intestinal microsomes.

Persistent inhibition of CYP3A4 by ketoconazole in modified Caco-2 cells.

PURPOSE: The intestinal metabolism of some CYP3A substrates can be altered profoundly by co-administration of the potent inhibitor, ketoconazole. The present research was conducted to test the hypothesis that, unlike the inhibition kinetics observed with isolated microsomes, inhibition of CYP3A4 by ketoconazole in an intestinal cell monolayer is time-dependent and slowly reversible. METHODS: Confluent, 1alpha,25-dihydroxy Vitamin D3-treated Caco-2 cells were exposed to 1 microM ketoconazole for two hours (Phase I) and then washed three times with culture medium containing no inhibitor. This was followed by a second incubation period (Phase II) that varied in the composition of the apical and basolateral culture medium: Condition 1. apical/basolateral differentiation medium (DM); Condition 2, apical/ basolateral DM + basolateral 2g/dL Human Serum Albumin (HSA); Condition 3, apical/basolateral DM + apical/basolateral 2 g/dL HSA. After various lengths of time for the second phase (0 to 4 hours), both apical and basolateral medium were exchanged with fresh DM. Midazolam (6 microM) was included in the apical medium for determination of CYP3A4 activity (Phase III). RESULTS: Two-way ANOVA of the data revealed persistent inhibition of CYP3A4 under Conditions 1 and 2 (p < 0.001). In contrast, cells treated under Condition 3 exhibited rapid reversal of CYP3A4 inhibition. The level of CYP3A4 activity observed was inversely correlated with the amount of ketoconazole remaining in the cell monolayer at the end of Phase II. CONCLUSIONS: These studies provide mechanistic evidence that ketoconazole can be sequestered into the intestinal mucosa after oral administration, producing a persistent inhibition of first-pass CYP3A4 activity.

Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition.

Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil.

BACKGROUND: Despite widespread use, little is known about the comparative pharmacokinetics of intrathecally administered opioids. The present study was designed to characterize the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection. METHODS: Equal doses of morphine and alfentanil, fentanyl, or sufentanil were administered intrathecally (L3) to anesthetized pigs. Microdialysis probes were used to sample cerebrospinal fluid at L2, T11, T7, T3, and the epidural space at L2 every 5-10 min for 4 h. At the end of the experiment, spinal cord and epidural fat tissue were sampled, and each probe's recovery was determined in vitro. Using SAAM II pharmacokinetic modeling software (SAAM Institute, University of Washington, Seattle, WA), the data were fit to a 16-compartment model that was divided into four spinal levels, each of which consisted of a caternary arrangement of four compartments representing the spinal cord, cerebrospinal fluid, epidural space, and epidural fat. RESULTS: Model simulations revealed that the integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution. CONCLUSIONS: The four opioids studied demonstrate markedly different pharmacokinetic behavior, which correlates well with their pharmacodynamic behavior.

Spinal cord bioavailability of methylprednisolone after intravenous and intrathecal administration: the role of P-glycoprotein.

BACKGROUND: High-dose intravenously administered methylprednisolone has been shown to improve outcome after spinal cord injury. The resultant glucocorticoid-induced immunosuppression, however, results in multiple complications including sepsis, pneumonia, and wound infection. These complications could be reduced by techniques that increase the spinal bioavailability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and plasma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylprednisolone from plasma into spinal cord. METHODS: The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bolus dose plus 5.4 mg x kg(-1) x h(-1)) and intrathecal (1-mg/kg bolus dose plus 1 mg x kg(-1) x h(-1)) methylprednisolone infusions were compared in pigs. In addition, wild-type mice and P-glycoprotein knockout mice were used to determine the role of P-glycoprotein in limiting spinal bioavailability of methylprednisolone. RESULTS: Despite the greater intravenous dose, concentrations of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administration in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 microg/g) and those lacking P-glycoprotein (2.83 +/- 0.46 microg/g). In contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of P-glycoprotein-deficient mice were similar to those in skeletal muscle (2.83 +/- 0.27 microg/g). CONCLUSIONS: These pig studies demonstrate that the spinal cord bioavailability of methylprednisolone is poor after intravenous administration. The studies in knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cord.