Automated radiochemical synthesis and biodistribution of [¹¹C]l-α-acetylmethadol ([¹¹C]LAAM).

Long-acting opioid agonists methadone and l-α-acetylmethadol (LAAM) prevent withdrawal in opioid-dependent persons. Attempts to synthesize [(11)C]-methadone for PET evaluation of brain disposition were unsuccessful. Owing, however, to structural and pharmacologic similarities, we aimed to develop [(11)C]LAAM as a PET ligand to probe the brain exposure of long-lasting opioids in humans. This manuscript describes [(11)C]LAAM synthesis and its biodistribution in mice. The radiochemical synthetic strategy afforded high radiochemical yield, purity and specific activity, thereby making the synthesis adaptable to automated modules.

In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R,S)-methadone, LAAM and their main metabolites.

Methadone and L-alpha-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.

Pharmacokinetic interactions between HIV antiretroviral therapy and drugs used to treat opioid dependence.

Injection drug use is a common risk factor for HIV infection, and opioid use and dependence is the underlying condition that often fuels HIV risk behaviour and subsequent HIV seroconversion among injection drug users (IDUs). Treatment of opioid dependence often requires continued opioid administration in the form of substitution therapy, which means that opioid-using IDUs often continue receiving opioids even after cessation of illicit drug use. The concurrent use of both antiretrovirals and opioids in HIV-positive individuals is thus common. This review was undertaken to summarise current knowledge on the interactions between the opioids and antiretrovirals and to make recommendations on the treatment of HIV-positive opioid-dependent patients.

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and delavirdine.

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p = .018) and increased the methadone elimination half-life (p < .001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p < .001), C(max) by 30% (p = .013), and C(min) by 59% (p = .004) while decreasing T(max) (p = .05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration.

Blood-brain equilibration kinetics of levo-alpha-acetyl-methadol using a chronically instrumented sheep preparation.

1.--The delayed onset and long duration of action of the opioid agonist levo-alpha-acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood-brain equilibration of LAAM itself. 2.--The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0-75 min) were measured using a validated HPLC assay. 3.--LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. 4.--Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood-brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min(-1)) and a large cerebral distribution volume (724 ml). 5.--In conclusion, pharmacokinetic-pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.

Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies.

OBJECTIVE: Levo-alpha-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequential N-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomal N-demethylation in vitro is catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humans in vivo is unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect. METHODS: Healthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model. RESULTS: Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity) 199 +/- 91 [control] versus 11.3 +/- 4.0 [rifampicin] and 731 +/- 229 ng . h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC(96)) [norLAAM + dinorLAAM] (859 +/- 241 versus 107 +/- 48 and 1185 +/- 179 ng . h/mL; p < 0.05) and clinical effects (mean miosis AUC(96) 128 +/- 40 versus 22.5 +/- 14.9 and 178 +/- 81 mm . h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations. CONCLUSION: CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.

Evaluation of levo-alpha-acetylmethdol (LAAM) as an alternative treatment for methadone maintenance patients who regularly experience withdrawal: a pharmacokinetic and pharmacodynamic analysis.

The aim of this study was to determine if substitution of daily methadone with second daily levo-alpha-acetylmethadol (LAAM) would convert non-holders on methadone into holders on LAAM, and to compare plasma concentration-time profiles of (R)-methadone with LAAM and its two metabolites. Sixteen stable methadone maintenance treatment participants (non-holders, n = 8) were randomly allocated to continue methadone for 3 months or switch to LAAM for 3 months, and then crossed over to the alternative drug for 3 months. At steady state, there were two testing sessions (24 h for methadone and 48 h for LAAM), during which opioid withdrawal severity, respiration rate and pupil diameter were measured 10-11 times and venous blood was collected 13-15 times. Ten age- and gender-matched controls underwent one 48-h test session. Areas under the withdrawal severity score versus time curve (AUC(0-47) hours for LAAM and controls; AUC(0-24) x 2 for methadone) were similar in holders on methadone and LAAM (P = 0.62), but were greater in non-holders when they were taking methadone than LAAM (P < 0.001). Respiratory depression and pupillary constriction were similar for LAAM and methadone. In comparison to (R)-methadone, plasma nor- and dinor-LAAM concentrations fluctuated little over the dosing interval. LAAM converted methadone non-holders into LAAM holders. LAAM may therefore be useful in selected MMT non-holders and improve retention in opioid treatment programs.

Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-alpha-methadol in opioid-naive individuals.

BACKGROUND: Levo-acetyl-alpha-methadol (LAAM) exerts most of it mu-agonist activity through the action of its 2 N-demethylation metabolites, norLAAM and dinorLAAM. The N-demethylation of LAAM to norLAAM and norLAAM to dinorLAAM is primarily performed by cytochrome P450s (CYP) in the 3A family. No previous studies have been conducted to determine the effect of in vivo inhibition of CYP3A on the pharmacokinetics and pharmacodynamics of LAAM. METHODS: Oral LAAM (5 mg/70 kg) was administered on 2 occasions in a single-blind, randomized crossover design to 13 opioid-naive subjects (6 women and 7 men) 1 hour after pretreatment with 400 mg ketoconazole or placebo. Blood and urine samples were collected at defined intervals over 240- and 96-hour periods, respectively; LAAM, norLAAM, and dinorLAAM concentrations were determined by liquid chromatography-tandem mass spectrometry. Physiologic and subjective measures were collected for up to 72 hours. RESULTS: Results are presented as the geometric mean with 90% confidence intervals of individual ratios of ketoconazole to placebo sessions. Coadministration of ketoconazole and LAAM resulted in a 3.22-fold (2.53-4.10, P <.001) and 5.29-fold (4.24-6.61, P <.001) increase in the maximum plasma concentration (Cmax) and area under the curve (AUC) of LAAM. The values for time to Cmax (tmax) of norLAAM and dinorLAAM were increased 2.43-fold (1.92-3.08, P <.001) and 11.6-fold (8.36-16.1, P <.001), with 0.77-fold (0.67-0.87, P <.005) and 0.55-fold (0.49-0.60, P <.001) decreases in their respective Cmax values. The AUCs of norLAAM and dinorLAAM were increased 2.25-fold (1.96-2.58, P <.001) and 1.21-fold (1.12-1.32, P <.005), respectively. Pupil diameter was significantly decreased by LAAM after both placebo and ketoconazole pretreatment; ketoconazole increased the tmax for miosis 2.92-fold (2.01-4.25, P <.001). Other physiologic measures and numerous subjective effects measures were significantly affected by LAAM; however, few significant effects of ketoconazole pretreatment were observed on these outcomes. CONCLUSION: A single dose of ketoconazole causes a significant pharmacokinetic drug interaction with a single dose of LAAM that results in increased LAAM concentrations relative to norLAAM and dinorLAAM at early time points. Coadministration also results in prolongation of the appearance of its active metabolites and a concomitant prolongation of miosis, a sensitive dynamic index of mu-opioid action. The clinically relevant increase in LAAM concentrations and prolongation of plasma LAAM metabolites may affect physiologic function, such as QT intervals, suggesting that coadministration of LAAM and CYP3A4 inhibitors should be contraindicated.

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir.

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.

Transfer of L-alpha-acetylmethadol (LAAM) and L-alpha-acetyl-N-normethadol (norLAAM) by the perfused human placental lobule.

The agonists buprenorphine and l-alpha-acetylmethadol (LAAM) were introduced as alternatives to methadone for treatment of the adult opiate addict. The direct and indirect effects of these drugs on normal fetal growth and development are currently under investigation in our laboratory. The goal of this report is to provide part of the data necessary to assess the safety of LAAM in treatment of the pregnant opiate addict. To achieve this goal, the technique of dual perfusion of placental lobule was utilized to determine the kinetics for transplacental transfer of LAAM and its effects on the viability and functional parameters of the tissue. LAAM is rapidly metabolized to the pharmacologically active norLAAM that was also included in this investigation. The two opiates were transfused at their plasma levels in patients under treatment, a concentration of 35 ng/ml. The drugs exhibited similar pharmacokinetic profiles, characterized by an initial phase of distribution into placental tissue followed by their low transfer to the fetal circuit. During the 4-h experimental period, the transfused tissue retained significant amounts of LAAM and norLAAM, and neither drug was metabolized. LAAM did not affect placental tissue viability and functional parameters. However, norLAAM caused a significant decrease in the release of human chorionic gonadotropin. At this time, it is unclear whether a similar effect for norLAAM may occur in vivo and, if so, what the consequences would be on its role in implantation and normal fetal growth and development.

The use of levo-alpha-acetylmethadol (LAAM) in methadone patients who have not achieved heroin abstinence.

Levo-alpha-acetylmethadol (LAAM) pharmacotherapy was offered to twelve patients who continued illicit opioid abuse after > or = eleven months in methadone maintenance treatment. After 6-8 weeks on LAAM, plasma concentrations of the norLAAM metabolite varied significantly by LAAM dosing day, plasma adrenocorticotropin (ACTH) concentrations were significantly increased compared to methadone, and two of the seven subjects remaining in LAAM treatment were free of illicit opioids and nonprescribed methadone. After one year, one of five remaining subjects was using illicit opioids, and three were using non-prescribed methadone. While subject acceptance of LAAM was high, subjects were not in a "steady-state," with evidence of ongoing illicit opioid abuse.

Developmental toxicity of levo-alpha-acetylmethadol (LAAM) in tolerant rats.

Mated Crl:CD VAF/Plus female rats, in a range-finding study (n = 5-6 per dose) and a subsequent definitive study (n = 30 per dose) were used to determine the developmental toxicity, including the teratogenic potential of levo-alpha-acetylmethadol (LAAM) hydrochloride, in tolerant rats. Tolerance was induced by initially administering the drug by gavage (10 ml/kg) at 2 mg/kg/day and increasing the dose every 2 weeks for 12 weeks until the doses of 2, 6, 9, 12, and 15, or 2, 6, and 12 mg/kg/day were achieved in the range-finding or definitive study, respectively. Females were then mated to stock males and treated throughout mating and gestation. Controls received distilled water on a similar regimen. The range-finding experiment was used for initial clinical evaluations and to determine tissue concentrations of LAAM and metabolites. In plasma, liver, and brain collected from dams and fetuses pooled by litter on gestation day 20, LAAM and its two N-demethylated metabolites, norLAAM and dinorLAAM, showed dose-dependent increases in concentration and in tissue to plasma ratios. Tissue to dam plasma ratios were highest in dam liver (17-60), intermediate in fetal liver (3-16), and fetal brain (3-14), and lowest in dam brain (0.8-5.6) and fetal plasma (0.3-2.1). In the definitive study, caesarean section examinations were performed following euthanization on gestation day 20 on all surviving females followed by teratologic examination of the fetuses. Drug-related outcomes, including increased activity, secondary hair loss, scabbing, focal swelling, and material around the nose, were exhibited by all groups receiving LAAM. Maternal toxicity was evident as decreased body weights, with maximum reduction at the 6-mg/kg/day dose, and reduction in feed consumption. There was also evidence of developmental toxicity in the form of postimplantation losses at all doses of LAAM. There were no deaths attributable to LAAM. No grossly observable visceral or skeletal anomalies related to LAAM were observed in the fetuses. In conclusion, the no-observable-effect level when administered to tolerant rats was less than 2 mg/kg/day with regard to clinical signs, body weight, body weight gain, and feed consumption, and with regard to developmental toxicity as reflected by postimplantation losses. Despite maternal and developmental toxicity, there was no evidence of selective fetal toxicity or teratogenic activity attributable to LAAM.

Intravenous and oral l-alpha-acetylmethadol: pharmacodynamics and pharmacokinetics in humans.

Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral administration than oral administration; however, preclinical studies suggest otherwise. This study examined the pharmacodynamic and pharmacokinetic profile of LAAM when given orally and intravenously to humans. Opioid-experienced volunteers (n = 6), who were not physically dependent on opioids, received LAAM (20 and 40 mg/70 kg i.v. and p.o.) and placebo under double-blind, double-dummy conditions during five weekly experimental sessions. Behavioral, physiological, subjective and pharmacokinetic measures were collected before and for 96 hr after drug administration. Intravenous LAAM produced significant subjective and physiological effects that appeared within 5 min, whereas the effects of oral LAAM appeared more slowly within 1 to 2 hr after drug administration. Pharmacokinetic data indicate that the immediate effects of intravenous LAAM are largely attributable to the parent drug rather than the active metabolites, nor-LAAM and dinor-LAAM. LAAM produced prototypic opioid agonist effects (i.e., miosis, subjective ratings of high, nodding) that were of equal magnitude across routes, dose-related and of long duration (up to 60 hr). These data are in contrast to previous clinical reports and indicate that LAAM produces effects of immediate onset when administered parenterally, which suggests that intravenous LAAM possesses greater abuse potential than previously believed.

Incorporation of drugs for the treatment of substance abuse into pigmented and nonpigmented hair.

Hair analysis for drugs may be useful for the long-term monitoring of recidivism and treatment compliance. L-alpha-Acetylmethadol, buprenorphine, and methadone are drugs that are used for the treatment of substance abuse. The purpose of this study was to study the relationship between dose, plasma concentration, hair concentration, and hair pigmentation for these compounds and their major metabolites in an animal model. Male Long-Evans rats received either L-alpha-acetylmethadol (1 and 3 mg/kg; n = 6), buprenorphine (1 and 3 mg/kg; n = 5), or methadone (4 and 8 mg/kg; n = 5) by intraperitoneal injection daily for 5 days. Fourteen days after beginning drug administration, newly grown hair was collected and analyzed for either L-alpha-acetylmethadol and two metabolites (L-alpha-acetyl-N-normethadol and L-alpha-acetyl-N,N-dinormethadol), methadone and two metabolites (D,L-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium and D,L-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline), or buprenorphine and one metabolite (norbuprenorphine). The plasma time course (AUC) for each compound was also determined after a single administration of each drug at the specified doses. There was an approximate dose-dependent increase in measured hair concentration of each parent drug in pigmented hair. The concentrations of L-alpha-acetylmethadol, methadone, and buprenorphine in nonpigmented hair were significantly less than that measured in pigmented hair at either the high or low dose. The metabolites L-alpha-acetyl-N-normethadol and D,L-2-ethyl-1,5dimethyl-3,3-diphenylpyrrolinium were detected at lower concentrations than their respective parent compounds (L-alpha-acetylmethadol or methadone) in pigmented hair. However, the L-alpha-acetyl-N,N-dinormethadol metabolite concentrations in pigmented hair were significantly greater than those of the parent drug after either the low or the high L-alpha-acetylmethadol dose. These data demonstrate that L-alpha-acetylmethadol, methadone, buprenorphine, and metabolites are distributed into hair in a dose-related manner with a preference for pigmented hair.

Managing illicit drug use. A practical guide.

Illicit drug use is spreading, especially in the developing world, but has begun to stabilise in most developed countries. The phenomenon of illicit drug use is still poorly understood, with responses in most countries influenced largely by cultural factors. A range of psychosocial and pharmacotherapeutic treatments is available; of these, methadone maintenance treatment for heroin dependence has the most evidence of benefit. A large body of literature--including some well designed studies--indicates that methadone reduces heroin use, mortality, criminal activity and risk of human immunodeficiency virus (HIV) infection. Methadone is more likely to be effective if higher doses, longer durations of treatment and more realistic goals are set. However, research findings which would improve outcomes considerably are often not implemented. Methadone maintenance programmes, which attract and retain more illicit drug users than other treatment modalities, are now being made more available in many countries in recognition of their therapeutic effectiveness and utility in reducing the spread of HIV infection among people injecting heroin. HIV infection is now recognised in many countries to be the most serious complication of illicit drug use for both individual drug injectors and their communities. Levo-alpha-acetylmethadol (LAAM) has similar properties to methadone but a longer half-life. This suggests a number of clinical benefits which would also reduce the cost of treatment. However, LAAM has not been approved by regulatory authorities for routine use despite positive findings in some studies. Buprenorphine has shown some promise in the management of heroin dependence but is still undergoing evaluation. It is, however, unlikely to ever be used widely for the management of illicit drug users. Naltrexone may have some advantages for special populations. Pharmacotherapeutic treatment for cocaine and amphetamine users is still at a developmental stage.