Diazepam and methadone interactions in methadone maintenance

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.     

Automated LC-MS method for the fast stereoselective determination of methadone in plasma.

Methadone (MTD) is a chiral drug widely used for the treatment of opioid dependence for which a rapid analytical method for the determination of each enantiomer would be advantageous. In order to improve method sensitivity and to automate the entire analytical process, a column-switching configuration has been developed. An online extraction system coupled to a cellulose-based chiral stationary phase (CSP), namely Chiralcel OJ-R, was used and detection was performed by mass spectrometry. Fifty microl of plasma were injected into the liquid chromatography-mass spectrometry (LC-MS) system after addition of acetonitrile (ACN) containing methadone deuterated D9 (MTD-D9) (internal standard) and centrifugation. For the rapid extraction step, a large particle size support was selected. A baseline separation of MTD enantiomers was obtained in less than 12 min. Trueness and precision were evaluated with control samples at 500 ng/ml of (R,S)-methadone. Trueness values were 106.6% and 103.0% for (R)-MTD and (S)-MTD, respectively, with a coefficient of variation inferior to 2.5% for both compounds. Finally, a good concordance was found using this method for analysis of plasma samples from patients in maintenance treatment as compared to a previously described HPLC-UV method after liquid-liquid extraction.     

Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects.

In vitro studies of drug metabolism with human liver microsomes can be performed in the early stages of drug development. Such experiments may reflect the in vivo metabolism of drugs in humans and thus allow for a prediction of drug disposition before the compound is administered to humans. We tested this hypothesis for the example of verapamil, which is a calcium channel blocker that undergoes extensive metabolism. Moreover, the drug is administered as a racemate, and stereoselective first-pass metabolism favoring the extraction of the more potent S-verapamil is observed after p.o. administration. To evaluate the in vitro metabolism, microsomes prepared from 10 human livers were incubated with both S- and R-verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro interactions between fluoxetine or fluvoxamine and methadone or buprenorphine

Summary— Methadone and buprenorphine, widely used in the treatment of opioid abuse, are metabolized by cytochrome P450 3A4, while fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors, are known to be P450 2D6 and 3A4 inhibitors in vitro. This study deals with the in vitro interactions between methadone or buprenorphine and fluoxetine or fluvoxamine. Fluoxetine inhibited methadone N -demethylation (K i = 55 μM), but conversely did not inhibit buprenorphine dealkylation. Norfluoxetine inhibited the metabolism of both methadone and buprenorphine metabolisms (K i 13 and 100 μM, respectively). Fluvoxamine inhibited methadone N -demethylation with a K i of 7 μM and buprenorphine dealkylation, uncompetitively, with a K i of 260 μM. Finally, these results suggest that care should be taken when selective serotonin reuptake inhibitors are administered in the treatment of drug craving. This is particularly true in the case of fluvoxamine which is more potent than fluoxetine in inhibiting methadone and buprenorphine metabolism.     

Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans

The effects of grapefruit juice (150 ml at -15, -10, -1/4, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo-controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)- and (R)-nitrendipine. There were highly significant differences in the area under the concentration-time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half-lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.     

The effects of methadone on maternal-fetal interactions in the rat.

Female Sprague-Dawley rats received methadone (25 mg/kg/day) by gavage throughout gestation. Water-gavaged rats served as controls. Fetuses were delivered by cesarean section when parturition was imminent. Our results indicate that methadone may interfere with fetal development and maternal-fetal interactions to some degree. The observed alterations were as follows: fetal growth retardation, an interference with the triggering of parturition once normal delivery size is attained and possible positional malformations.     

Effects of methadone on human cigarette smoking and subjective ratings

In order to study possible interactions between opioids and cigarette smoking, we examined the effects of oral methadone administration on the smoking behavior of five male methadone-maintenance patients. Isolated subjects smoked their regular brand of cigarettes ad libitum in a naturalistic laboratory environment while reading or watching television. Ninety minutes before each daily 2-hr smoking session subjects received either placebo, dextromethorphan (a taste blind) or one of three doses of methadone, 0.5, 1.0 or 2.0 times their regular maintenance dose (40-60 mg). Each subject received each treatment five times, in a mixed order across days. Methadone pretreatment resulted in a dose-related increase in the number of cigarettes smoked per session (from a mean of 2.8 after placebo to 5.6 after the high dose of methadone). The total time spent puffing during the session increased from a mean of 27 sec after placebo to 74 sec after the high dose of methadone. CO levels in expired air (a measure of actual smoke inhalation) showed corresponding dose-related increases. Methadone administration also resulted in dose-related decreases in pupil diameter and increases in subjective ratings of smoking satisfaction and dose-strength. Dextromethorphan had no significant effects on any measure of smoking behavior or subjective response. The results demonstrate that methadone can produce substantial increases in cigarette smoking and may have implications regarding the proposed role of endogenous opioids in the smoking process.     

Calcium metabolism in hypertension and allied metabolic disorders

Data suggest a critical role for Ca metabolism in the pathophysiology of hypertensive disease. Intracellularly, all hypertension displays elevated cytosolic free-Ca2+ and suppressed free-Mg2+ levels. Extracellularly, however, heterogeneous defects in Ca and Mg metabolism are observed. This apparent divergence may be explained by considering all hypertension as the expression, in varying degrees, of two underlying Ca-related mechanisms: one (salt sensitive, low renin, Ca(2+)-antagonist sensitive) dependent on inappropriate cellular Ca2+ uptake from the extracellular space and the other (salt insensitive, renin dependent, Ca(2+)-antagonist insensitive) dependent on increased cellular Ca2+ release from intracellular sites. Recent work highlights the role of 1,25-dihydroxyvitamin D3 and the newly described parathyroid hypertensive factor in volume-dependent low-renin forms of hypertension. Altered cellular ion handling may also explain metabolic and clinical correlates of hypertension, e.g., peripheral insulin resistance, hyperinsulinemia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). Thus, all subjects with NIDDM, whether hypertensive or not, display the same elevated cytosolic free-Ca2+ and suppressed free-Mg2+ levels observed in hypertension. Furthermore, adiposity, the level of blood pressure, and fasting and postglucose hyperinsulinemia are all closely and quantitatively related to intracellular free-Ca2+, free-Mg2+, and pH levels. This suggests a broader hypothesis, in which hypertension, obesity, insulin resistance, and NIDDM, each usually considered a distinct clinical entity, represent different clinical expressions of a common defect in cellular ion handling, hence explaining their frequent clinical coexistence in the general population.     

Mechanistic studies on metabolic interactions between gemfibrozil and statins

A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (approximately 4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [(14)C]SVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.     

Porphyrin metabolism in men with metabolic syndrome

Forty-three patients with metabolic syndrome (MS) were examined. The urinary (uroporphyrin--UP and coproporphyrin--CP) and fecal (CP and protoporphyrin) fractions of porphyrin, as well as the urinary excretion of porphyrin precursors (S-aminolevulinic acid and porphobilinogen) were measured. Porphyrin metabolic disturbances were registered in 33 (76.7%) patients. Nine of these patients displayed such qualitative changes as fraction mismatch (CP/UP < 1; the normal value is 2.1 +/- 0.4), and an increase in the level of porphyrin precursors, while their total urinary porphyrin level was normal. In 24 patients pathological changes in porphyrin exchange were characterized by such quantitative changes as a many-fold increase in urinary and/or fecal porphyrin fraction as well as the development of secondary biochemical coproporphyrinuria syndromes, symptomatic elevation of fecal porphyrin level, and latent late cutaneous porphyria. Changes in porphyrin exchange in patients with metabolic syndrome broaden the scope of disturbances occurring in this syndrome, and allow considering these changes as additional criteria.     

PPAR gamma and human metabolic disease

The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARalpha, PPARdelta, and PPARgamma) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARalpha and PPARdelta appear primarily to stimulate oxidative lipid metabolism, while PPARgamma is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARgamma in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARgamma in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.     

The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans

In this clinical investigation, four groups of subjects (eight young women and eight young men [age range, 18 to 25 years], and eight elderly women and eight elderly men [greater than 60 years of age]) received single oral doses (400 mg) of racemic mephobarbital. The apparent total body clearance of R-mephobarbital was much greater and the elimination half-life was much shorter in the young men compared with the other three groups. This enantiomer displayed an age-dependent gender effect and a gender-dependent age effect in its metabolism. The apparent total body clearance of the S-enantiomer was much lower than that of the R-enantiomer in all subjects and did not differ between subject groups, although the elimination half-life was slightly but significantly shorter in young males. A consequence of these enantiomeric differences was an apparently enhanced stereoselectivity in the metabolism of mephobarbital in young men. These substantial influences of age and gender on the stereoselective disposition of mephobarbital are consistent with recent findings concerning the expression and regulation of cytochrome P450 enzymes.     

Increased analgesia and alterations in distribution and metabolism of methadone by desipramine in the rat.

Treatment of rats with desipramine (DMI) 1 hour before the subcutaneous administration of methadone increased the intensity and prolonged the duration of methadone analgesia, as determined by the hot plate method. DMI significantly reduced the analgesic ED50 of methadone from a control value of 3.4 to 1.6 or 0.5 mg/kg in rats treated with 20 or 30 mg/kg of DMI, respectively. DMI treatment also significantly reduced the LD50 of methadone. DMI (20 mg/kg i.p.) was given 1 hour prior to administration of 14C-methadone (5 mg/kg s.c.) and the distribution of total 14C, unchanged methadone and methadone metabolites in various tissues was studied. DMI treatment greatly increased the brain uptake of 14C and the methadone brain/plasma concentration ratios for up to 3 hours. The concentrations of 14C and unchanged methadone were higher in kidneys and lower in lungs of DMI-treated rats as compared to controls. However, the ratios of unchanged methadone to its metabolites in kidneys and lungs were not changed significantly by DMI treatment. The level of unchanged methadone in liver was markedly elevated by DMI treatment at 45 and 90 minutes (190 and 183% of controls, respectively). The level of a water-soluble glucuronide metabolite of methadone was significantly decreased at 45-, 90- and 180-minute intervals (37, 36 and 54% of controls, respectively.) However, the total 14C in liver and the concentrations of two N-demethylated metabolites of methadone were not changed significantly. In vitro addition of DMI to liver microsomal incubations resulted in inhibition of the N-demethylation of methadone. It is suggested that DMI potentiated and prolonged methadone analgesia by increasing the brain concentration of methadone and by inhibiting metabolism of methadone in the liver.     

Cerebral metabolic interactions between thyroid state and imipramine in the rat

Local rates of cerebral glucose metabolism were determined in four groups of adult rats 4 weeks after surgery: sham-operation + saline; thyro-parathyroidectomy (TX) + saline; sham-operation + imipramine; or TX + imipramine. Daily i.p. injections, imipramine at 10 mg/kg or saline at 1 ml/kg b.w., were given during the 2 weeks before the deoxyglucose experiment. TX reduced glucose utilization in the limbic, motor, endocrine and auditory systems. Imipramine reduced glucose metabolism in the median eminence, both habenular nuclei and several limbic regions including the amygdala, hippocampus and parietal cortex. Five structures showed significant interactions between TX and imipramine. In three of these regions, the supraoptic nucleus, central amygdala and lateral habenula; TX and/or imipramine individually reduced metabolism and the combined treatment raised it back to within the normal range. In the dorsal raphe, TX and imipramine tended to increase metabolism and the combined treatment resulted in a decrease to within normal range. The neurohypophysis, unaffected by TX alone, showed a significant increase in activity when TX was combined with imipramine. These data indicate, in part, that both hypothyroidism and imipramine treatment alone depress metabolism in limbic forebrain and the major limbic-brainstem relay nuclei. Combined treatment normalizes metabolism in many of these limbic pathways. Hypothetically, hypothyroidism may alter central catecholamine function in such a way that the metabolic response to imipramine is reversed or altered.