Norbuprenorphine Concentrations Research Articles

Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers

PurposeBuprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. MethodsBoth studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. FindingsIn the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0–∞, AUC0–last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers. ImplicationsThe absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.

Triple dosing with high doses of buprenorphine: Withdrawal and plasma concentrations.

In maintenance treatment for opiate addiction, buprenorphine can be administered less frequently than daily due to its long half-life. To examine the plasma concentration of buprenorphine and norbuprenorphine for 72 hours after a dose of 72 mg and to objectively and subjectively evaluate the correlations between concentrations and withdrawal levels. Patients in maintenance treatment with buprenorphine with a daily dose of 24 mg were given a triple dose of 72 mg (n = 9), in an outpatient setting. Blood samples were drawn, and withdrawal symptoms were evaluated objectively and subjectively every 24 hours over 72 hours. Urine and blood toxicology samples were obtained. The triple dose was generally accepted well with low subjective and objective withdrawal scores. However, two patients aborted the study on day 3 and reported withdrawal symptoms. Benzodiazepine use was confirmed in one while the other likely used unauthorized buprenorphine. Administration of buprenorphine in three times the daily dose seems acceptable, also in the higher daily maintenance doses (here, 24 mg) used in many clinical settings. Two patients did not tolerate the regimen but, partly due to the outpatient setting, the reasons why are unclear. Further research should be of interest as high buprenorphine doses are becoming more common clinically.

Pharmacokinetic-pharmacodynamic modelling of intravenous buprenorphine in conscious horses

ObjectiveDescribe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects. Study designSingle phase non-blinded study. AnimalsSix dedicated research horses, aged 3–10 years and weighing 480–515 kg. MethodsThermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 & 60 minutes and 2, 4, 6, 8, 12 & 24 hours post-administration of 10 μg kg−1 buprenorphine IV. Intestinal motility was measured 1, 6, 12 & 24 hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10 μg kg−1 IV and 1, 2, 4, 6, 10, 15, 30, 45 & 60 minutes, and 2, 4, 6, 8, 12 & 24 hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration–time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model. ResultsPlasma buprenorphine concentrations were detectable to 480 minutes in all horses and to 720 minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15 minutes post-buprenorphine administration until the 8–12 hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0 Newtons (median: 4.4 N); and was associated with plasma buprenorphine concentrations in the range 0.34–2.45 ng mL−1. Conclusions and clinical relevanceThe suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.

The Impact of Recent Cocaine Use on Plasma Levels of Methadone and Buprenorphine in Patients with and Without HIV-infection

Cocaine decreases methadone and buprenorphine plasma concentrations. HIV infection and/or antiretroviral medication use may impact these relationships. We sought to determine the association between recent cocaine use and methadone and buprenorphine concentrations in HIV-infected and uninfected subjects in clinical care. R- and S-methadone or buprenorphine and norbuprenorphine concentrations were assessed at 0.5, 1, 2, and 24hours after dosing in subjects with confirmed cocaine use and abstinence. We compared methadone and buprenorphine concentrations for cocaine use vs. abstinence, by HIV status in 16 subjects receiving methadone (6 HIV-infected) and 17 receiving buprenorphine (8 HIV-infected). With recent cocaine use, peak R-methadone (244 vs. 297ng/mL, p=0.03) and peak S-methadone (285 vs. 339ng/mL); p=0.03 concentrations were lower in HIV-uninfected subjects only. Peak buprenorphine and norbuprenorphine concentrations were unchanged regardless of cocaine use or HIV status. Cocaine may decrease methadone concentrations in HIV-uninfected subjects. HIV infection or its treatment may attenuate cocaine's effect on methadone.

Improved buprenorphine immunoassay performance after urine treatment with β-glucuronidase.

Buprenorphine (BUP), a semi-synthetic opioid analgesic, is increasingly prescribed for the treatment of chronic pain and opioid dependence. Urine immunoassay screening methods are available for monitoring BUP compliance and misuse; however, these screens may have poor sensitivity or specificity. We evaluated whether the pretreatment of urine with β-glucuronidase (BG) improves the sensitivity and overall accuracy of three BUP enzyme immunoassays when compared with liquid chromatography-tandem mass spectrometry (LC-MS-MS). Urine samples sent to our laboratories for BUP testing (n = 114) were analyzed before and after BG pretreatment by cloned enzyme donor immunoassay (CEDIA), enzyme immunoassay (EIA) and homogenous EIA (HEIA) immunoassays using a common 5 ng/mL cutoff. Total BUP and norbuprenorphine (NBUP) concentrations were measured by LC-MS-MS as the reference method. Urine BG pretreatment improved EIA, HEIA and CEDIA sensitivities from 70, 82 and 94%, respectively, to 97% for each of the three methods, when compared with LC-MS-MS. While the specificity of the EIA and HEIA remained 100% after BG pretreatment, the specificity of the CEDIA decreased from 74 to 67%. Urine pretreatment with BG is recommended to improve sensitivity of the EIA and HEIA BUP screening methods.

(115) Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic non-cancer pain

The use of buprenorphine for the management of chronic pain has risen rapidly since the FDA approved a transdermal formulation of this opioid in 2010. Consensus guidelines for the use of chronic opioid therapy highlight the importance of routine monitoring for patience compliance using periodic urine drug screens. The validity of the urine buprenorphine detection assay, currently in widespread use, was established for monitoring patient compliance in patients receiving sublingual formulations (e.g. subutex, suboxone) in the outpatient addiction treatment setting. However, transdermal dosing is an order of magnitude lower (mcg range) than sublingual (mg range). This retrospective analysis of tandem LC-MS urine samples from a single reference laboratory compares the results from two different buprenorphine treatment cohorts: transdermal pain treatment and sublingual detoxification. Samples from the group (n=54) undergoing pain treatment with the transdermal formulation showed urine concentrations of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine glucuronide significantly lower than the range of those treated with sublingual preparations (often below the 5mcg/ml limit of detection). The analyte that differed the most between the two patient groups was norbuprenorphine, detected in only 16.2% of transdermal patients with an overall median concentration of < 3 ng/mL, versus 100% of sublingual patients with a median concentration of 88 ng/mL. Buprenorphine-glucuronide demonstrated the highest positive rate of detection at 97.3% in samples from the transdermal group with at least one positive detectable analyte. This study demonstrates that urine parent drug and metabolite profiles are markedly different for the distinct patient populations using sublingual and transdermal buprenorphine formulations. Failure to recognize the difference in urine concentrations may lead to a misinterpretation of noncompliance. Assays with high sensitivity for buprenorphine glucuronide will likely have greater relevance in the pain treatment setting. The use of buprenorphine for the management of chronic pain has risen rapidly since the FDA approved a transdermal formulation of this opioid in 2010. Consensus guidelines for the use of chronic opioid therapy highlight the importance of routine monitoring for patience compliance using periodic urine drug screens. The validity of the urine buprenorphine detection assay, currently in widespread use, was established for monitoring patient compliance in patients receiving sublingual formulations (e.g. subutex, suboxone) in the outpatient addiction treatment setting. However, transdermal dosing is an order of magnitude lower (mcg range) than sublingual (mg range). This retrospective analysis of tandem LC-MS urine samples from a single reference laboratory compares the results from two different buprenorphine treatment cohorts: transdermal pain treatment and sublingual detoxification. Samples from the group (n=54) undergoing pain treatment with the transdermal formulation showed urine concentrations of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine glucuronide significantly lower than the range of those treated with sublingual preparations (often below the 5mcg/ml limit of detection). The analyte that differed the most between the two patient groups was norbuprenorphine, detected in only 16.2% of transdermal patients with an overall median concentration of < 3 ng/mL, versus 100% of sublingual patients with a median concentration of 88 ng/mL. Buprenorphine-glucuronide demonstrated the highest positive rate of detection at 97.3% in samples from the transdermal group with at least one positive detectable analyte. This study demonstrates that urine parent drug and metabolite profiles are markedly different for the distinct patient populations using sublingual and transdermal buprenorphine formulations. Failure to recognize the difference in urine concentrations may lead to a misinterpretation of noncompliance. Assays with high sensitivity for buprenorphine glucuronide will likely have greater relevance in the pain treatment setting.

Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

BackgroundPrescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. MethodsPlasma was collected for 72h after administration of placebo or 2, 4, 8, 12, or 16mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography–tandem mass spectrometry with limits of quantitation of 0.1μg/L. ResultsMaximum buprenorphine concentrations (mean±SE) were detected 10min after 2, 4, 8, 12, 16mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15min (3.7±0.7μg/L) after 16mg IV administration. ConclusionsBuprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12mg.

Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood–brain barrier in mice

Deaths due to asphyxia as well as following acute poisoning with severe respiratory depression have been attributed to buprenorphine in opioid abusers. However, in human and animal studies, buprenorphine exhibited ceiling respiratory effects, whereas its metabolite, norbuprenorphine, was assessed as being a potent respiratory depressor in rodents. Recently, norbuprenorphine, in contrast to buprenorphine, was shown in vitro to be a substrate of human P-glycoprotein, a drug-transporter involved in all steps of pharmacokinetics including transport at the blood-brain barrier. Our objectives were to assess P-glycoprotein involvement in norbuprenorphine transport in vivo and study its role in the modulation of buprenorphine-related respiratory effects in mice. University-affiliated research laboratory, INSERM U705, Paris, France. Wild-type and P-glycoprotein knockout female Friend virus B-type mice. Respiratory effects were studied using plethysmography and the P-glycoprotein role at the blood-brain barrier using in situ brain perfusion. Norbuprenorphine(≥ 1 mg/kg) and to a lesser extent buprenorphine (≥ 10 mg/kg) were responsible for dose-dependent respiratory depression combining increased inspiratory (TI) and expiratory times (TE). PSC833, a powerful P-glycoprotein inhibitor, significantly enhanced buprenorphine-related effects on TI (p < .01) and TE (p < .05) and norbuprenorphine-related effects on minute volume (VE, p < .05), TI, and TE (p < .001). In P-glycoprotein-knockout mice, buprenorphine-related effects on VE (p < .01), TE (p < .001), and TI (p < .05) and norbuprenorphine-related effects on VE (p < .05) and TI (p < .001) were significantly enhanced. Plasma norbuprenorphine concentrations were significantly increased in PSC833-treated mice (p < .001), supporting a P-glycoprotein role in norbuprenorphine pharmacokinetics. Brain norbuprenorphine efflux was significantly reduced in PSC833-treated and P-glycoprotein-knockout mice (p < .001), supporting P-glycoprotein-mediated norbuprenorphine transport at the blood-brain barrier. P-glycoprotein plays a key-protective role in buprenorphine-related respiratory effects, by allowing norbuprenorphine efflux at the blood-brain barrier. Our findings suggest a major role for drug-drug interactions that lead to P-glycoprotein inhibition in buprenorphine-associated fatalities and respiratory depression.

Buprenorphine exposure in infants of opioid‐dependent mothers at birth

Buprenorphine, a partial opioid agonist used in treating opioid dependence, is not approved in Australia for use in pregnancy. Nevertheless, many pregnant women choose to remain on the drug. To investigate cord/maternal transfer ratios for buprenorphine and norbuprenorphine in women at delivery. Maternal and cord serum samples were collected from 10 maternal-infant pairs at delivery. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Maternal and infant demographic information was collected. Linear regression was used to assess the relationship between maternal and cord measurements. Median (interquartile range) maternal age was 27 (23.8-32) years, with 90% of the women on buprenorphine before pregnancy. Median infant birthweight was 3148 (3088-3545) g and 60% of infants had neonatal abstinence requiring admission to a neonatal intensive care unit for a median of 8.5 (2.5-16.3) days. Median maternal buprenorphine daily dose was 8.5 mg (range 1-28 mg). Mean (95% confidence interval) cord serum concentrations of buprenorphine and norbuprenorphine were 0.4 (0.3-0.5) μg/L and 1.2 (0.9-1.4) μg/L, respectively. Mean maternal concentrations of buprenorphine and norbuprenorphine were 1.0 (0.6-1.4) μg/L and 1.2 (0.9-1.4) μg/L, respectively. Mean cord/maternal ratios were 0.43 (0.36-0.5) for buprenorphine and 0.53 (0.43-0.63) for norbuprenorphine. Maternal buprenorphine and norbuprenorphine concentrations and ratio of buprenorphine/norbuprenorphine explained 85.7, 69.6 and 94.4%, respectively, of variation in the corresponding cord concentrations. Usual therapeutic doses of buprenorphine administered to pregnant women resulted in low concentrations of buprenorphine and norbuprenorphine in maternal serum and a low transfer to the fetal circulation (cord plasma) at birth.

Estimated Dose Exposure of the Neonate to Buprenorphine and Its Metabolite Norbuprenorphine via Breastmilk During Maternal Buprenorphine Substitution Treatment

The aim of the present study was to estimate the dose of buprenorphine and its primary metabolite norbuprenorphine that a breastfed infant would receive during maternal maintenance treatment with buprenorphine. Seven pregnant opioid-dependent women taking buprenorphine (median, 7 mg/day; range, 2.4-24 mg) and who intended to breastfeed were recruited. After lactation was established, several milk samples were collected from each subject over a 24-hour dose interval, and buprenorphine and norbuprenorphine concentrations were measured by liquid chromatography-tandem mass spectrometry. The average concentration (C(avg)) across the dose interval was estimated as for both buprenorphine and norbuprenorphine (as buprenorphine equivalents). Absolute infant dose (AID), defined as C(avg) × daily milk intake, and relative infant dose (RID), defined as 100×AID/weight-adjusted maternal daily dose, via milk were calculated, assuming a milk intake of 0.15 L/kg/day. The infant's health and progress were assessed directly and by questionnaire on the study day. Mean (95% confidence interval) norbuprenorphine concentration in milk and AID values (1.94 [0.79-3.08] μg/L and 0.29 [0.12-0.46] μg/kg/day, respectively) were approximately half those for buprenorphine (3.65[1.61-5.7] μg/L and 0.55 [0.24-0.85] μg/kg/day, respectively). Similarly, the mean RID values were 0.18% (0.11-0.25%) for norbuprenorphine and 0.38% (0.23-0.53%) for buprenorphine. The breastfed infants showed no adverse effects, were all in good health, and were progressing as expected. Thus the dose of buprenorphine and norbuprenorphine received via milk is unlikely to cause any acute adverse effects in the breastfed infant.

Neonatal outcome of 58 infants exposed to maternal buprenorphine in utero

To study the neonatal outcome of infants exposed to buprenorphine in utero. We prospectively followed 54 buprenorphine-using pregnant women and their 58 infants. Urinary buprenorphine and norbuprenorphine concentrations in the mothers were measured prior to delivery, and in the infants during the first 3 days of life. The Finnegan score was used to evaluate neonatal abstinence syndrome. Other medical problems as well as social outcomes were recorded. All infants had buprenorphine in their urine. A total of 38 infants required 20 +/- 10 days (range 7-48 days) of morphine treatment for neonatal abstinence syndrome. The length of hospital stay for all infants was 25 +/- 19 days (range 3-125 days). The infants' highest urinary norbuprenorphine concentrations across their first 3 days of life correlated with the length of hospital stay and duration of morphine treatment (both p < 0.05). The mean birth weight and mean head circumference (n = 58) were below average (mean -0.7 standard deviation [SD] and mean -0.5 SD, respectively). Eleven infants were discharged home, 19 infants were placed in foster care and 28 infants were discharged with their mothers to Mother and Child homes or to other institutions. Maternal buprenorphine use at the time of birth may cause neonatal abstinence syndrome, requiring long-term hospitalization. Multiple social problems require a multidisciplinary team approach.

Buprenorphine and Norbuprenorphine in Hair of Pregnant Women and Their Infants after Controlled Buprenorphine Administration

Buprenorphine is under investigation as a pharmacotherapeutic agent for treating opioid dependence in pregnant women. We hypothesized that there would be a relationship between the cumulative maternal dose of buprenorphine during pregnancy and the concentration of buprenorphine and norbuprenorphine in maternal and infant hair. This study examined buprenorphine and norbuprenorphine concentrations in hair obtained from 9 buprenorphine-maintained pregnant women and 4 of their infants. Specimens were analyzed by liquid chromatography-tandem mass spectrometry with limits of quantification of 3.0 pg/mg. All maternal hair specimens were washed with methylene chloride before analysis, and when sufficient amounts of maternal hair were available, specimens also were analyzed without washing. Infant hair specimens were not washed. Buprenorphine concentrations were significantly greater in unwashed hair than washed hair (P = 0.031). Norbuprenorphine concentrations were significantly greater than buprenorphine concentrations in both maternal (P = 0.0097) and infant hair (P = 0.0033). There were statistically significant associations between the cumulative maternal dose of buprenorphine administered and the concentrations of buprenorphine (washed, P <0.0001; unwashed, P = 0.0004), norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005), and buprenorphine plus norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005) for both washed and unwashed maternal hair specimens. There was a significant positive association between concentrations of buprenorphine and norbuprenorphine in maternal hair (washed, P <0.0001; unwashed, P = 0.0003), a trend for this association in infant hair (P = 0.08), and an association between buprenorphine concentrations in maternal unwashed hair and infant hair (P = 0.0002). The buprenorphine:norbuprenorphine ratio increased in distal segments. Buprenorphine treatment during gestation provides an opportunity for monitoring drug disposition in maternal and fetal tissues under controlled conditions.

Prevalence and Disposition of Drugs of Abuse and Opioid Treatment Drugs in Oral Fluid

Testing oral fluid for drugs of abuse has been studied under many conditions but rarely has been evaluated in large population databases. We evaluated oral fluid tests in a database from a commercial laboratory in the United Kingdom composed of 8679 confirmed positive results. The results originated from 635,000 specimens collected over the period of May 2004 through September 2006. Oral fluid specimens were collected with the Intercept oral fluid collection device, screened by enzyme immunoassay, and confirmed by GC-MS or GC-MS-MS. The database was organized by collection settings (legal/treatment, N = 8198 specimens; and workplace, N = 481 specimens) and by drug groups (without consideration of collection setting). The drug groups were as follows (number of confirmed positives): amphetamines (468); benzodiazepines (892); buprenorphine (276); cannabinoids (725); cocaine (1443); methadone (998); and opiates (5739). The goal of the study was to provide drug/metabolite prevalence data, concentrations, and drugs/metabolite patterns encountered in oral fluid. Comparison of results by collection setting indicated differences in relative frequency, primarily for opiates and cannabinoids. Opiate positives were most frequently observed for specimens collected in legal/treatment settings, whereas cannabinoids were most frequently reported in the workplace. An array of information on drug and metabolite occurrences and concentration arose from evaluation of the data by drug groups. Amphetamine was the predominant drug reported for the Amphetamines Group; approximately 10% were also positive for MDA and/or MDMA; and methamphetamine was rarely reported. Multiple combinations of diazepam, nordiazepam, oxazepam, temazepam, chlordiazepoxide, and lorazepam were reported for the Benzodiazepine Group. Buprenorphine, an opioid treatment drug, was the predominant analyte reported, but low concentrations of norbuprenorphine were frequently reported. THC was the predominant analyte reported in the Cannabinoids Group and was frequently reported in combination with cannabidiol and cannabinol. THCCOOH was reported in only 10.8% of these specimens and was never reported in the absence of THC. HO-THC was reported in 5.7% of the specimens. In the Cocaine Group, cocaine was present, often in combination with BZE, but also as the sole analyte in 17.3% of the specimens. AEME and cocaethylene were reported in 10.4% and 5.5% of the specimens. Methadone, another opioid treatment drug, was reported in all specimens for the Methadone Group; EDDP was reported in 30.1% of the specimens. In the Opiates Group, morphine, codeine and 6-acetylmorhine were most frequently reported, often in combination. The frequency of detection of 6-acetylmorphine when morphine was present (N = 4575 specimens) was 77.5%. Surprisingly, heroin (19.0%; N = 1091 specimens) and 6-acetylcodeine (24.9%; N = 1431 specimens) were frequently reported. The results from analysis of this large oral fluid database offer a rich mixture of new information on detection frequency, drug and metabolite patterns, and concentration data on drugs of abuse.

Basic pharmacology of buprenorphine

Buprenorphine is a derivative of the morphine alkaloid thebaine. The plasma elimination half-life of buprenorphine is three times longer than that of the active metabolite, norbuprenorphine. Although the elimination of norbuprenorphine from the body is more rapid than that of buprenorphine, the plasma concentration of norbuprenorphine was observed to exceed that of buprenorphine with chronic administration of buprenorphine. This plasma level of norbuprenorphine is based on the proportional increase in norbuprenorphine-glucuronide observed after one enterohepatic circulation of buprenorphine due to the first-pass metabolism. When buprenorphine and norbuprenorphine were administered intraventricularly, the analgesic effect of norbuprenorphine was approximately one-fourth that of buprenorphine. After intravenous administration of buprenorphine or norbuprenorphine in rats, the analgesic effect of norbuprenorphine was approximately 1/50th that of buprenorphine. The remarkably weak analgesic effect of norbuprenorphine after intravenous administration may be due to the low permeability of norbuprenorphine into the brain. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. The most dangerous side effect of opioid therapy is respiratory depression. In our study of the respiratory effects after intravenous infusion in rats, norbuprenorphine was ten times more potent than the parent drug. However, it is possible that the plasma levels of norbuprenorphine with chronic administration of buprenorphine are not sufficiently high to depress respiratory function. Overall, buprenorphine is a safe and highly effective analgesic opioid for the treatment of chronic pain.

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers ( n = 10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls ( n = 10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine ( p < 0.001, p < 0.001), norbuprenorphine ( p = 0.026, p = 0.006), buprenorphine glucuronide ( p = 0.002, p < 0.001), and norbuprenorphine glucuronide (NS, p = 0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.

Simultaneous determination of buprenorphine, norbuprenorphine and the enantiomers of methadone and its metabolite (EDDP) in human plasma by liquid chromatography/mass spectrometry

A previously reported enantioselective LC–MS assay for the determination of ( R)- and ( S)-methadone [Met] and ( R)- and ( S)-2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine [EDDP] (the primary metabolite of Met) has been adapted for use in the simultaneous determination of the plasma concentrations of Met, EDDP, buprenorphine (Bu) and norbuprenorphine (norBu). All of the target compounds were separated within 15 min using an α 1-acid glycoprotein chiral stationary phase, a mobile phase composed of acetonitrile: ammonium acetate buffer [10 mM, pH 7.0] in a ratio of 18:82 (v/v), a flow rate of 0.9 ml/min at 25 °C. Deuterium labeled compounds were used as internal standards [d 4-Bu, d 3-norBu, ( R, S)-d 3-Met and ( R, S)-d 3-EDDP] and linear relationships between peak height ratios and drug concentrations were obtained for Bu and norBu in the range 0.2–12 ng/ml with correlation coefficients greater than 0.999. The relative standard deviations (%R.S.D.) for the intra- and inter-day precision of the method were <4.5% and for accuracy was <4.0%. The method was validated and used to analyze plasma samples obtained from opioid dependent methadone-maintained adults enrolled in a research study.

Effect of psychotropic medication on the in vitro metabolism of buprenorphine in human cDNA-expressed cytochrome P450 enzymes

The aim of the present study was to estimate the drug interaction potential of psychtropic medication on buprenorphine (BUP) N-dealkylation using cDNA-expressed cytochrome P450 (CYP) enzymes. BUP was incubated with psychotropic drugs and cDNA-expressed CYP 3A4 and CYP 2C8 enzymes. Seven substances were screened for their inhibition potency. To check for a mechanism-based component in inhibition, all substances were tested with and without preincubation, respectively. Norbuprenorphine (NBUP) concentrations were determined by liquid chromatography/tandem mass spectrometry, following liquid/liquid extraction. Midazolam and zolpidem demonstrated greatest inhibition in screening experiments. As expected, IC(50) values without preincubation were higher than those after 30-min preincubation, with zolpidem 113.1 microM and midazolam 20.25 microM. Following a 30-min preincubation period in the absence of the probe substrate BUP, the apparent IC(50) values for zolpidem and midazolam were 20.17 microM and 3.5 microM. Both midazolam and zolpidem showed a distinct inhibitory potency towards NBUP formation by CYP 3A4, implicating a decreased conversion of BUP. When preincubated, the inhibitory potency was increased, which strongly suggests a metabolically activated component in inhibition.

Validation of the Immunalysis(R) Microplate ELISA for the Detection of Buprenorphine and Its Metabolite Norbuprenorphine in Urine

The purpose of this study was to validate the Immunalysis Buprenorphine Microplate enzyme-linked immunosorbent assay (ELISA) for the detection of buprenorphine in urine samples. Sixty-nine urine samples were obtained from volunteers on the Subutex treatment program and from routine samples submitted to the laboratory for buprenorphine testing. For ELISA analysis, samples were diluted 1:10 with K(2)HPO(4) (0.1M, pH 7.0). The limit of detection was calculated as 0.5 ng/mL buprenorphine. The intra-assay and interday precision was 3.8% (n = 10) and 8.6% (n = 50) respectively at 1 ng/mL buprenorphine. At a low concentration of norbuprenorphine (1 ng/mL), the immunoassay demonstrated a cross-reactivity of 78%. A higher cross-reactivity of 116% was observed at a higher concentration of norbuprenorphine (10 ng/mL). Dihydrocodeine, codeine, tramadol, morphine, propoxyphene, methadone, and EDDP were tested at concentrations of 10 ng/mL and 10,000 ng/mL and demonstrated no cross-reactivity with the assay. For liquid chromatography-tandem mass spectrometry (LC-MS-MS), deuterated internal standard mixture, 1M acetate buffer (pH 5.0), and b-glucuronidase were added to the standards and samples, which were then incubated for 3 h at 60 degrees C. After incubation, 3 mL K(2)HPO(4) (0.1M, pH 6.0) was added and the pH altered to pH 6.0 using 1M KOH. Buprenorphine and norbuprenorphine were subsequently extracted by solid-phase. Twenty-one samples were confirmed positive and 48 samples were confirmed negative by LC-MS-MS. Using a cut-off value of 0.5 ng/mL buprenorphine, the immunoassay demonstrated a sensitivity and specificity of 100%.

Buprenorphine and Norbuprenorphine Concentrations in Human Breast Milk Samples Determined by Liquid Chromatography-Tandem Mass Spectrometry

Buprenorphine (BUP) is considered to be safe during pregnancy. However, the extent of BUP transfer into breast milk has not been investigated thoroughly. Because the drug concentration in the milk is 1 of the determinants in the assessment of the exposure risk, a rapid and sensitive LC-MS/MS method has been developed and evaluated to measure BUP and norbuprenorphine (norBUP) concentrations in milk. A solid-phase and 2 liquid-liquid extraction procedures have been compared. The lower limits of detection and quantification were 0.05 ng/mL and 0.18 ng/mL for BUP and 0.05 ng/mL and 0.20 ng/mL for norBUP, respectively, using a sample volume of 0.5 mL milk. BUP and norBUP concentrations determined from 10 random breast milk samples collected over 4 successive days from a lactating woman during buprenorphine maintenance therapy ranged from 1.0 to 14.7 and 0.6 to 6.3 ng/mL, respectively. Drug exposure of the infant may be considered to be low. Further investigations may seek to extend these preliminary findings to evaluate an infant's level of BUP exposure through breast milk.