Factors associated with persistent opioid use 6-12 months after primary total knee arthroplasty.

Persistent pain following knee arthroplasty occurs in up to 20% of patients and may require ongoing analgesia, including extended opioid administration. A comprehensive secondary analysis was performed from results of a study that considered persistent postoperative pain in 242 patients who underwent unilateral knee arthroplasty using a standardised enhanced recovery programme. Opioid prescribing for 12 months before and 12 months after surgery was evaluated and converted to oral morphine equivalents. Demographic, functional, psychological and pain questionnaires were completed along with quantitative sensory testing and genetic analysis. Forty-nine percent of patients had at least one opioid prescription in the 12 months before surgery. Opioid prescriptions were filled in 93% of patients from discharge to 3 months and in 27% of patients ≥6 months after surgery. Persistent opioid use ≥6 months after surgery was strongly associated with pre-operative opioid use (RR 3.2, p < 0.001 (95%CI 1.9-5.4)). The median (IQR [range]) oral morphine equivalent daily dose was 3.6 (0.9-10.5 [0-100.0]) mg pre-operatively, 35.0 (22.5-52.5 [4.6-180.0]) mg in hospital, 12.8 (5.1-24.8 [0-57.9]) mg from discharge to 3 months and 5.9 (4.5-12.0 [0-44.5]) mg at ≥6 months following surgery. Predictors of increased daily oral morphine equivalent ≥6 months after surgery included increased average daily oral morphine equivalent dose compared with previous values (lag), increased body mass index and three or more comorbid pain sites. Persistent opioid use was not associated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (RR 1.003, p = 0.655, 95%CI 0.65-1.002) or WOMAC function (RR 1.001, p = 0.99, 95%CI 0.99-1.03) outcomes 6 months after surgery. There was no association between persistent opioid use and pre-operative quantitative sensory testing results or psychological distress. Pre-operatively, patients with a higher body mass index, more comorbid pain sites and those who had filled an opioid prescription in the last 12 months, were at increased risk of persistent opioid use and a higher oral morphine equivalent daily dose ≥ 6 months after surgery. Strategies need to be developed to limit dose and duration of persistent opioid use in patients following knee arthroplasty surgery.

Persistent postoperative pain after total knee arthroplasty: a prospective cohort study of potential risk factors.

BACKGROUND: Persistent postoperative pain (PPP) is common after total knee arthroplasty (TKA). The primary aim of this prospective cohort study was to identify important predictors of moderate to severe PPP 6 and 12 months after TKA. METHODS: Consenting patients (n=300) undergoing primary unilateral TKA attended a preoperative session to collect clinical information (age, gender, BMI, preoperative knee pain, comorbid pain, likely neuropathic pain) and psychological variables (depression, anxiety, catastrophising, expected pain). Quantitative sensory testing (pressure pain thresholds, temporal summation, conditioned pain modulation) was performed, and blood samples were obtained for subsequent genotyping of OPRM1 and COMT. Acute postoperative pain was measured at rest and during movement. Surgical factors (surgery time, patella resurfacing, anaesthetic type) were collected after operation. Follow-up questionnaires were sent 6 and 12 months after surgery. Multivariate logistic regression was used to identify predictors of PPP. RESULTS: The prevalence of moderate to severe PPP was 21% (n=60) and 16% (n=45) 6 and 12 months after surgery, with 55% (n=33) and 60% (n=31) of PPP likely neuropathic in nature. At 6 months, a combination of preoperative pain intensity, expected pain, trait anxiety, and temporal summation (Akaike information criterion, 309.9; area under receiver operating characteristic (ROC) curve, 0.70) was able to correctly classify 66% of patients into moderate to severe PPP and no to mild PPP groups. At 12 months, preoperative pain intensity, expected pain, and trait anxiety (Akaike information criterion, 286.8; area under ROC curve, 0.66) correctly classified 66% of patients. CONCLUSIONS: Findings from this study highlight several factors that may be targeted in future intervention studies to reduce the development of PPP. TRIAL REGISTRY NUMBER: ACTRN12612001089820.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

OBJECTIVE: This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. METHOD: Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. RESULTS: Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. CONCLUSION: Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach.

Opioid activation of toll-like receptor 4 contributes to drug reinforcement.

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells.

BACKGROUND: The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints. METHODS: Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells. RESULTS: Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors. CONCLUSION: On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.

Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep.

BACKGROUND: CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. METHODS: The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg(-1) (2 min infusion) of CNS 7056 in alternating order on separate days. RESULTS: CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min(-1) and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min(-1), and inter-compartmental clearances of 2.85 and 1.44 litre min(-1), while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) was 0.10 µg ml(-1). CONCLUSIONS: CNS 7056 has PK-PD properties compatible with its potential human use as a short-acting i.v. sedative.

Benzodiazepine dependence: focus on withdrawal syndrome.

Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or years of regular or repeated use. The socioeconomic costs of the present high level of long-term benzodiazepine use are considerable. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased. However, many physicians continue to prescribe benzodiazepines and patients wishing to withdraw receive little advice or support. Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly persons, pregnant women, children, alcohol- or drug-dependent patients and patients with comorbid psychiatric disorders. The following update gives recent research results on the withdrawal pathophysiology and practical information in order to treat or prevent benzodiazepine withdrawal syndrome.

Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone.

OBJECTIVE: To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. METHODS: In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. RESULTS: The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered. CONCLUSIONS: CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.

Blood-brain distribution of morphine-6-glucuronide in sheep.

BACKGROUND AND PURPOSE: At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep. EXPERIMENTAL APPROACH: Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements. KEY RESULTS: A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2. CONCLUSION AND IMPLICATIONS: Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.

Attitudes toward the care of patients with acquired immunodeficiency syndrome. A survey of community internists.

Community physicians may play an increasing role in treating patients with acquired immunodeficiency syndrome (AIDS) because of the shift away from inpatient care. At a community hospital in New York, NY, we surveyed 230 attending physicians in a department of medicine to determine their attitudes toward the care of patients with AIDS. Factor analysis produced three clusters of attitudes termed antipathy, liability, and isolation. These factors, together with physicians' "knowledge" and background, were analyzed as predictors of treating patients with AIDS. While antipathy, isolation, and fear of acquiring AIDS were not predictors, liability scores were inversely correlated with the likelihood of treating the disease (r = -.18). Liability was influenced by patients' attitudes toward AIDS. Primary care physicians had higher liability and isolation scores than subspecialists and were more likely to see support groups, guaranteed funding, and education as incentives to treat patients with AIDS. Further study is needed to target measures that support primary care physicians in their care of patients with this disease.

Pharmacogenetics of opioid response.

For opioids requiring CYP2D6 O-demethylation to active metabolites, poor metabolizers have reduced metabolite formation and minimal pain reduction. Clinically, this has only reliably been shown for tramadol. Ultra-rapid metabolizers have an increased risk of toxicity especially for codeine. ABCB1 genetics show no consistent findings. In Asian populations, the high OPRM1 118A>G frequency associates with higher opioid dosage requirements. Clinical translation of opioid genetics is premature because many important pain and addiction phenotype factors contribute.

Stereoselective inhibition of pindolol renal clearance by cimetidine in humans.

There are few data on whether differences exist in the renal tubular secretion of enantiomers and no data on whether inhibition of renal secretion of individual enantiomers is stereoselective. Pindolol was used as a probe drug because it is used clinically as a racemic mixture of R-(+) and S-(-) enantiomeric forms and is highly secreted by the proximal tubules of the kidney. Eight young healthy subjects received a single 15 mg oral dose of racemic pindolol with and without 400 mg cimetidine twice daily. The area under the plasma concentration-time curve of both R-(+)- and S-(-)-pindolol were significantly (p less than 0.01) increased by cimetidine from 234 +/- 90 (mean +/- SD) to 344 +/- 78 ng/ml.hr for R-(+)-pindolol and from 209 +/- 73 to 288 +/- 69 ng/ml.hr for S-(-)-pindolol. The renal clearance of R-(+)-pindolol (170 +/- 55 ml/min) was significantly (p less than 0.05) less than that for S-(-)-pindolol (222 +/- 66 ml/min). Cimetidine significantly (p less than 0.01) reduced the renal clearances of R-(+)-pindolol to 104 +/- 18 ml/min and for S-(-)-pindolol to 155 +/- 38 ml/min. The enantiomer with the higher renal clearance [S-(-)-pindolol] had its renal clearance reduced less by cimetidine (26% versus 34%, p less than 0.05). Cimetidine appears to have a stereoselective action on the active transport system for organic cations in the proximal tubule.

Gastric acid inhibition and oxmetidine kinetics in duodenal ulcer.

Gastric acid inhibitory effects and kinetics of oxmetidine, a new histamine H2-receptor antagonist, were examined in five patients with duodenal ulcer disease. A constant intravenous infusion of impromidine was used to stimulate gastric acid secretion for 6 hr. Oxmetidine was then given in a 28-mg IV infusion and a 200-mg oral solution. The maximum inhibition of gastric acid output was, on average, 77% after infusion and 92% after oral doses, with similar values for volume inhibition. Mean overall percent inhibition of acid output, volume, and H+ concentration was 22%, 8%, and 15% for the intravenous dose and 51%, 33%, and 29% for the oral dose. The effect lasted for 3 hr after the intravenous dose and for 5 hr after the oral dose. Mean values for systemic clearance and half-life were 161 ml/min and 2.3 hr. An average of 4.3% of the dose was recovered in urine as unchanged drug and 27% was recovered as a glucuronide metabolite. Mean bioavailability was 36%. Plasma concentration for 50% inhibition of acid output was 0.50 microgram/ml, indicating that oxmetidine is 2.5 times as potent as cimetidine. No adverse effects were noted during the study.

Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene.

A chronic-dosing pharmacokinetic study was carried out in six healthy subjects to examine the potential for cimetidine to reduce the CLR and CLH of triamterene. Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine significantly reduced the clearance of triamterene by hydroxylation by 32% (P less than 0.016) and the CLR of triamterene by 28% (P less than 0.063), with no change in its protein binding. The CLR of the active sulfate conjugate of triamterene was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine, suggesting a decreased absorption. These results are consistent with cimetidine inhibiting cytochrome P-450 enzymes in the liver and also competing with triamterene for renal tubular secretion. Despite the pharmacokinetic interaction, cimetidine caused minimal alteration to the natriuretic and antikaliuretic effects of triamterene.

Cimetidine plasma concentration-response relationships.

Cimetidine plasma concentration-response relationships were investigated in six healthy subjects using suppression of gastric acid secretion under continuous pentagastrin stimulation (1.5 micrograms/kg/hr) as a test model. With the Hill equation the sigmoid was preferable to the linear relationship between plasma concentration and effect, and there were significant correlations of 0.78 micrograms/ml (range 0.54 to 1.04 micrograms/ml) for 50% inhibition of gastric acid secretion was determined; mean concentration for 90% inhibition was calculated to be 3.9 micrograms/ml. The model described should allow determination of whether different patient populations (e.g., healthy subjects, patients with ulcers, male and female patients, patients with renal or liver disease) differ from one another in concentration-response relationships to histamine H2-receptor antagonists, so that appropriate drug plasma levels should be achieved for specific degrees of inhibition of gastric acid secretion.

The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans.

OBJECTIVES: We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan. METHODS: Six extensive metabolizers were studied on four occasions: (1) after 30 mg dextromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg quinidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor metabolizers were studied on two occasions: (1) after 30 mg dextromethorphan and (2) after placebo. Blood and urine were collected over 168 hours and assayed for dextromethorphan, total (conjugated and unconjugated) dextrorphan, 3-methoxymorphinan, and total 3-hydroxymorphinan. On each occasion at each blood sampling time, capsaicin was administered as an aerosol to provoke cough. RESULTS: Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers. For dextrorphan (as total), the AUC was reduced 8.6-fold in poor metabolizers; quinidine had no effect on the AUC. The median half-life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metabolizers given quinidine, and 1.4 hours in extensive metabolizers. The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers. There was a strong (r2 = 0.82) and significant (p < 0.01) positive correlation between the prestudy urinary metabolic ratios and the partial clearances of dextromethorphan to dextrorphan. There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model. CONCLUSION: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.

Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships.

OBJECTIVE: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity. METHODS: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid Emax model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated. RESULTS: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h). CONCLUSIONS: In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.

Elimination of amphotericin B in impaired renal function.

The influence of impaired renal function on the steady-state plasma clearance of amphotericin B was determined in seven patients with creatinine clearances ranging from zero to normal. Contrary to previous reports, steady-state plasma concentrations of total drug were lower in uremic patients than in patients with normal renal function. Total plasma clearance of amphotericin B ranged from 16.7 to 39.9 ml/min, correlated directly with the plasma creatinine concentration, and correlated inversely with the creatinine clearance. Urinary excretion of unchanged drug accounted for less than 10% of the dose. In 10 healthy subjects, mean percent of amphotericin B unbound in plasma was 3.55 +/- 0.32 (SD). Binding was determined in a further group of 10 uremic patients. Mean unbound percent (4.15 +/- 0.73, SD) was higher than in the healthy subjects, and the binding ratio (molar concentration of bound to unbound drug) correlated weakly with the creatinine clearance. This suggests that plasma clearance of unbound amphotericin B and, therefore, steady-state plasma concentrations of unbound drug are not affected by renal impairment, and that dosage requirements will be overestimated if based on measurements of total drug plasma concentration.

Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique.

BACKGROUND AND AIMS: The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism, and transport of drugs by the intestinal wall. METHODS: In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20-cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [(2)H(7)]verapamil was given intravenously. Blood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites. RESULTS: The mean fraction of the verapamil dose absorbed from the 20-cm segment was 0.76 but substantial interindividual variability (0.51-0.96) was shown. Bioavailability was low (19.3%). The intestinal wall contributed to the same extent as the liver to extensive first-pass metabolism (mean extraction ratio, 0.49 versus 0.48). Substantial transport of verapamil metabolites from the systemic circulation via the enterocytes into the intestinal lumen was observed. Compared with biliary excretion, intestinal secretion into a 20-cm jejunal segment contributed to drug elimination to a similar extent. CONCLUSION: First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.

The effect of old age on the disposition and antinociceptive response of morphine and morphine-6 beta-glucuronide in the rat.

The aims of this study were to examine the effect of old age on the pharmacokinetics of morphine and morphine-6 beta-glucuronide (M6G) and their relationships to antinociceptive activity. Morphine (21.0 mumol/kg) or M6G (21.7 mumol/kg) were administered s.c. to young adult and aged male Hooded-Wistar rats. Antinociceptive effect was measured by the tail-flick method at various times up to 2.5 h or 6.5 h after morphine or M6G administration, respectively, and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and brain were determined by HPLC. Creatinine clearance was significantly lower by 33% or 21% in aged compared to young adult rats receiving morphine or M6G, respectively. After morphine administration, the areas under the (i) antinociceptive effect-time curve, (ii) plasma morphine concentration-time curve, and (iii) brain morphine concentration-time curve were not different between young adult and aged rats. However, the AUC for plasma M3G was five-fold higher in the aged relative to young adult rats, which could not be accounted for by only a 33% lower creatinine clearance. M6G was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain. For M6G administration, the areas under the (i) antinociceptive effect-time curve, and (ii) plasma M6G concentration-time curve were 1.8- and 1.6-fold higher in aged compared to young adult rats, respectively. Concentrations of M6G in brain were below the limit of quantification. No morphine or M3G was detected in any of the plasma or brain samples of rats administered M6G. The results demonstrate no change in morphine antinociception and pharmacokinetics with age, and suggest that blood-brain barrier permeability and reception sensitivity to morphine are not altered in aged rats. Accumulation of M3G in plasma of aged rats is probably due to diminished renal clearance of M3G in addition to a reduction in the biliary excretion of M3G. The heightened sensitivity of the aged rats to M6G is probably due to the observed altered kinetics of M6G rather than a pharmacodynamic change.