Mexiletine effects on theophylline disposition

The effect of mexiletine administration on steady-state plasma theophylline concentrations was studied in eight normal healthy men in a prospective open label nonrandomized two-way crossover trial. Repeated doses of 300 mg of sustained-release theophylline were given every 12 hours for 9 days. Mexiletine hydrochloride, 200 mg every 8 hours, was given for five consecutive doses starting on the morning of day 6. Mexiletine increased theophylline levels in all subjects. Mean predose (trough) levels rose from 8.1 +/- 0.1 microgram.ml-1 to 13.4 +/- 0.6 micrograms.ml-1 and AUC(0-12) from 96.8 +/- 9.1 to 160.2 +/- 3.7 micrograms.ml-1.hr. Plasma clearance was reduced by mexiletine from 44.7 +/- 5.1 to 25.4 +/- 1.2 ml.hr-1. Both N-demethylated metabolites of theophylline were decreased by 60% by mexiletine, whose levels remained within its therapeutic range. Theophylline levels returned to pre-mexiletine values when this drug was discontinued. Mexiletine reduces theophylline clearance and increases its plasma concentration by inhibiting N-demethylation of theophylline. Plasma theophylline levels should be monitored when mexiletine is added.     

Clonidine effects on sulfobromophthalein disposition in mice

Increasing doses of clonidine enhanced the retention of sulfobromophthalein (BSP) in plasma and liver, while reducing elimination of this dye into bile. The ED50 of clonidine for these effects was 0.05 to 0.2 mg/kg s.c. In clonidine-treated mice which were warmed to reverse drug-induced hypothermia, plasma and liver BSP levels were raised as compared to saline-treated mice. Clonidine also raised plasma and liver levels of the BSP analog, dibromosulfophthalein, which is not conjugated before biliary elimination. Hepatic glutathione levels, activity of glutathione-S-transferase and ratios of conjugated to unconjugated BSP were not affected by clonidine. In mice with cannulas in their common bile ducts to prevent duct spasm, clonidine reduced the amounts of BSP eliminated into bile. Thus, the alpha-2 adrenoceptor agonist, clonidine, raised plasma and liver levels of anionic dyes and reduced their levels in bile by mechanisms other than altered conjugation, hypothermia or bile duct spasm.     

Opioid effects on lidocaine disposition and toxicity in mice

Morphine sulfate, 20 mg/kg, or equivalent doses of the opioids, meperidine and fentanyl, elevated plasma levels of lidocaine after i.v. administration of this antiarrhythmic drug. Plasma levels of the lidocaine metabolites, monoethylglycinexylidine and glycinexylidine, were reduced by opioids as lidocaine levels were elevated. The opioid antagonist, naloxone, 1 mg/kg, reversed the effects of morphine, 20 mg/kg, on lidocaine. After morphine, plasma levels of both lidocaine and indocyanine green were elevated, suggesting that the effect of morphine on lidocaine disposition was related to reduced hepatic blood flow. Morphine and meperidine increased lethality of i.v. lidocaine, as shown by marked reduction of LD50 by either opioid.     

Narcotic effects on hepatic disposition of sulfobromophthalein in rats

Ascending morphine doses above 5 mg/kg s.c. progressively reduced plasma clearance of sulfobromophthalein (BSP) and raised hepatic levels of this dye in rats. The narcotic reduced the elimination constant of BSP without affecting its volume of distribution. Because abdominal surgery markedly reduced plasma clearance of BSP, no further effect of morphine could be shown in rats with bile cannulas. In duct-cannulated animals morphine had no effect on BSP concentration in bile, but did raise hepatic BSP levels while reducing bile flow and biliary BSP content. The narcotic also lowered the biliary transport maximum of BSP. The effects on BSP disposition were demonstrated acutely after morphine administration but had subsided completely by 1 and 2 days after giving narcotic. The present findings suggest that morphine impaired the secretion of BSP into bile by a mechanism not involving biliary occlusion and thereby enhanced retention of this dye in liver and plasma.     

Opioid effects on hepatic disposition of dyes in mice

Morphine administration acutely reduced plasma clearance of sulfobromophthalein (BSP) in mice and increased hepatic retention of this dye. Increasing morphine doses from 5 to 40 mg/kg s.c. progressively raised plasma and liver BSP levels. Morphine-treated mice, warmed to reverse hypothermia, still had higher plasma and liver BSP levels. The narcotic also raised plasma levels of two dyes which are not conjugated, indocyanine green and dibromosulfophthalein. Naloxone reversed morphine-induced elevation of plasma BSP levels. In bile duct-ligated mice, plasma BSP levels were very high but hepatic BSP levels remained low, both after saline or morphine. Thus, the effects of morphine on BSP disposition differed from those of biliary occlusion. BSP content in bile was reduced by morphine, as dye levels were raised in plasma and hepatic parenchyma. In bile duct-cannulated mice morphine increased BSP levels in plasma and liver whereas reducing the amount of dye eliminated in bile.     

Influence of tobacco abstinence on the disposition kinetics and effects of nicotine

Habitual tobacco smoking accelerates the metabolism of many drugs. With tobacco abstinence, it was expected that nicotine metabolism would be slower than when smoking. To test this hypothesis, the disposition kinetics of intravenous nicotine were studied in 20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six subjects) when smoking again. Cardiovascular responses to nicotine were also measured. Unexpectedly, total and nonrenal clearance of nicotine increased by 36% and 39%, respectively, during abstinence. The increase in clearance after brief abstinence suggests that nicotine or its metabolites or another component of cigarette smoke inhibits nicotine metabolism in smokers. Cardiovascular responses to nicotine were greater after 1 week compared with overnight abstinence, consistent with loss of tolerance.     

Concentration-time effects of quinidine disposition kinetics in rhesus monkeys.

The effects of dose and duration of drug administration (time) on the disposition kinetics of quinidine were investigated in unanesthetized rhesus monkeys. A specific thin-layer chromatography-fluorometric assay was developed for the determination of quinidine in plasma, blood and urine. After the monkeys receive an i.v. bolus dose of 3 to 7 mg/kg, quinidine distributes rapidly in the body (T 1/2alpha = 2 minutes). The half-life associated with elimination (T 1/2 beta) was 27 to 35 minutes and primarily involved metabolic transformation. The volume of distribution varied between 0.2 and 0.65 liters/kg and total clearance between 4.8 and 13 ml/min/kg. Similar estimates of T 1/2 beta, clearance and volume of distribution were obtained following constant infusions producing steady-state concentrations less than 6 microng/ml. Prolonged infusion of quinidine at rates producing plasma concentrations in the range of 6 to 13 microng/ml resulted in increases in the elimination half-life whereas drug clearance remained constant. This observation suggests an increased volume of distribution. Both concentration and time were demonstrated to be important in producing changes in quinidine disposition kinetics. The precise mechanism underlying this phenomenon remains unanswered.     

Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol

The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.     

Effect of cirrhosis and debrisoquin phenotype on the disposition and effects of pinacidil

Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent. It is metabolized in humans to pinacidil N-oxide. To determine whether pinacidil's metabolism or effects were influenced by either liver disease or the subject's debrisoquin phenotype, eight patients with chronic stable cirrhosis and 13 healthy subjects were studied. Seven of the healthy volunteers were extensive metabolizers of debrisoquin, whereas six were of the poor metabolizer phenotype. Neither the clearance of pinacidil nor the production of the N-oxide was altered by the subjects' debrisoquin phenotype. Cirrhosis produced a 50% reduction in pinacidil's clearance (20.7 +/- 1.4 vs. 42.1 +/- 5.1 L/hr; P less than 0.0005) and a prolongation in the elimination t1/2 from 3.9 +/- 0.3 to 6.1 +/- 0.6 hours (P less than 0.01). Less pinacidil was metabolized to the N-oxide metabolite in the patients with cirrhosis than in the normal individuals. Thus pinacidil's metabolism and clearance are reduced in patients with cirrhosis but are independent of debrisoquin phenotype.     

Tolerance to morphine effects on renal disposition of xenobiotics in mice

Morphine administration (20 mg/kg s.c.) slowed renal elimination of phenol red in mice, raising plasma levels of this dye and reducing its levels in urine. After 9 days of twice daily morphine injections up to 100 mg/kg, an acute 20 mg/kg morphine challenge did not produce analgesia or hypothermia as in naive mice. This multiple dose morphine regimen also induced tolerance to the effects of the narcotic on plasma and urine levels of phenol red. Morphine, 20 mg/kg, reduced plasma p-aminohippurate clearance by 72% in naive mice but only by 56% in tolerant mice. However, reduction of iothalamate clearance after an acute morphine challenge did not show a statistically significant difference between naive and tolerant mice. These findings suggest that tolerance is more readily induced to the effects of narcotic on renal blood flow and/or tubular function than to reduction of glomerular filtration. Tolerance to the acute effects of morphine on phenol red disposition is probably due to lessened response of blood flow or tubular function in chronically dosed mice.     

Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.

CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacodynamic effects were determined over 6 h. Codeine-apparent clearance and partial metabolic clearance by O-demethylation were significantly greater in the Caucasian than in the Chinese subjects (1939 +/- 175 ml/min versus 1301 +/- 193 ml/min, p <.03 and 162.7 +/- 36.6 ml/min versus 52.7 +/- 12.7 ml/min, p <.02, respectively). Codeine's respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chinese subjects (p <.05), but no interethnic differences were noted in codeine's effect on the digit symbol substitution test and pupillary ratio. No morphine or morphine metabolites were detected in plasma when codeine was coadministered with quinidine. Codeine O-demethylation was significantly reduced after quinidine in both ethnic groups; however, the absolute decrease was greater in Caucasians (115.8 +/- 25.9 ml/min versus 46.8 +/- 10.6 ml/min, respectively, p <.03). The diminished production of morphine after quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p <.01). In conclusion, Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine. In addition, quinidine induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in Caucasians.     

Long-term neuronal effects and disposition of ectopic preproNGF gene transfer into the rat septum

Although NGF gene therapy has been proposed to treat age- or disease-related brain cholinergic decline, little is known about the ectopic expression or function of this trophic factor after transduction in the brain especially over long intervals. The neuron-targeting, recombinant adeno-associated virus serotype 2 (rAAV2) vector was used to express mouse NGF with C-terminal myc-tag in septum using a full-length preproNGF sequence. While the predominant form of endogenous NGF immunoreactivity in septum was 31 kd of proNGF, almost all of the ectopic NGF-immunoreactivity attributable to the rAAV2-mediated transduction in this region was recovered as mature NGF. Transgene expression was found in both cholinergic and GABAergic neurons, with the number of transduced neurons dependent on vector dose. To determine the long-term effects of this NGF-expression on neuron function, fimbria-fornix (FF) lesions were conducted 6 months after NGF gene transfer. NGF gene transfer attenuated the lesion-induced loss of septal cholinergic but not GABAergic neurons, indicating that long-term expression did not eliminate this response, which has been noted over short intervals. The effects and dose dependency of NGF gene delivery on neuroprotection and neurotrophism were also examined. NGF transduction increased cholinergic cell size in the septum, but required a higher vector dose than neuroprotection. These results reveal potential long-term benefits as well as concerns for genetically modifying septal NGF gene expression to preserve neuronal viability and function.     

Age and cibenzoline disposition

Oral cibenzoline kinetics were followed in 36 healthy subjects aged from 22 to 78 yr divided into groups of six subjects per decade between 20 and 80 yr. Each received a single, oral, 160-mg dose of cibenzoline. Blood and urine samples were collected for 72 hr. Cibenzoline plasma and urine concentrations were measured by HPLC. Maximum plasma cibenzoline concentrations (Cmax) ranged from 283 to 1100 ng/ml and occurred 1 to 2.5 hr after dosing. Apparent oral clearance (ClT) ranged from 401 to 1677 ml/min and the t 1/2 ranged from 5.9 to 13.4 hr. Nonrenal clearance (ClNR) ranged from 65 to 1113 ml/min, renal clearance (ClR) ranged from 165 to 645 ml/min, and 31% to 86% of the dose was recovered unchanged in urine (Xu). The volume of distribution (Vd) was large, ranging from 236 to 948 l. There was a significant relationship between age and the following kinetic parameters: Cmax, Xu, t 1/2 (all of which increased with age), ClT, ClR, ClNR, the terminal elimination rate constant beta, and Vd (which decreased with age). Mean ClT was 999 +/- 371 ml/min in the 20- to 30-yr age group and was 465 +/- 78 ml/min in the 70- to 80-yr age group. The change in ClT with age resulted from a decreased in both ClR and ClNR. Mean t 1/2 varied from 7 hr in the youngest group to 10.5 hr in the oldest group. The age-related changes in cibenzoline kinetics occurred over the entire age range studied and the relationship between age and these kinetic parameters appeared to be linear.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of probenecid on the disposition of risperidone and olanzapine in healthy volunteers

STUDY DESIGN: The metabolic pathways of most xenobiotics and endogenous compounds can be divided into phase 1 (oxidative, reductive, and hydrolytic) and phase 2 (glucuronidation, sulfate conjugation, glycine and glutathione conjugation, and acetylation and methylation) processes. Oxidative metabolism by the cytochrome P450 system has been intensively investigated compared with glucuronidation and other conjugation pathways. The primary aim of this study was to evaluate the disposition of olanzapine or risperidone in healthy volunteers with and without coadministration of the uridine diphosphoglucuronate-glucuronosyltransferase inhibitor probenecid. We hypothesized that olanzapine disposition would be altered as a result of decreased glucuronidation, whereas risperidone disposition would be relatively unaffected. METHODS: Our objective was to investigate whether this interaction would occur in 12 healthy volunteers, aged 22 to 42 years, who participated in a single-dose, randomized, 4-period, double-blind, crossover study receiving a single dose of either 5 mg olanzapine or 1 mg risperidone with and without 500 mg probenecid (8 doses over 4 days). Multiple blood samples were analyzed by means of liquid chromatography-tandem mass spectrometry or HPLC to assess the 48-hour time course of risperidone and olanzapine. Urine was assayed for free and glucuronidated drugs. RESULTS: When olanzapine was administered with probenecid, statistically significant differences were observed between plasma pharmacokinetic parameters compared with olanzapine administered alone (maximum concentration, P <.05; area under the plasma concentration-time curve from time zero to 24 hours, P <.01). Clearance was not significantly different between the treatment phases. Risperidone pharmacokinetic parameters were not significantly different (all parameters, P >.05). CONCLUSION: Inhibition of uridine diphosphoglucuronate-glucuronosyltransferase appeared to influence the disposition of olanzapine but not risperidone. Phase 2 metabolism may significantly influence the disposition of antipsychotic drugs and may be an important aspect of the variability in metabolism, participation in drug-drug interactions, and clinical response to some antipsychotic agents.     

Renal disposition and effects of naproxen and its l-enantiomer in the isolated perfused rat kidney

Renal handling, metabolism and effects on kidney function of naproxen and its l-enantiomer were examined in the isolated perfused rat kidney (IPK). Urinary excretion rate of naproxen was much lower than the filtration rate, indicating extensive reabsorption. Naproxen is accumulated considerably in the IPK. This accumulation is concentration-dependent and is probably the result of active secretion of naproxen. Considerable amounts of desmethyl-naproxen were formed in the IPK. The kinetic behavior of the l-enantiomer of naproxen did not differ from naproxen. Addition of 37.5 to 3750 micrograms naproxen caused a decrease in urinary flow, glomerular filtration rate and fractional excretion of sodium, chloride, potassium, magnesium and calcium. The presence of prostaglandin E2 in the perfusate fully opposed the effects of naproxen on kidney function. Addition of 375 micrograms l-enantiomer of naproxen did not influence kidney function. Addition of very high doses (1 x 10(5) micrograms) of naproxen and its l-enantiomer to the IPK caused diuresis and increased the fractional excretion of sodium, chloride, potassium, glucose and calcium. We conclude that the pharmacokinetic behavior and the metabolism of naproxen in the IPK is probably not stereoselective; that relatively low doses of naproxen exert a specific, stereoselective effect on kidney function caused by inhibition of the prostaglandin E2 synthesis and that high doses of naproxen exert a nonstereoselective effect on kidney function.     

Acute effects of indomethacin on the disposition of a potassium load.

We examined the effects of acute indomethacin administration on the disposition of a potassium load in anesthetized rats. In response to the potassium load, indomethacin-treated animals had greater plasma potassium concentrations and smaller increases in fractional excretion of potassium than did vehicle-treated rats, but there was no change in urine flow rate. Findings were consistent with indomethacin-induced impairment of renal potassium excretion. The effects of indomethacin in adrenalectomized animals were comparable to those that were observed in intact rats, which indicates that inhibition of aldosterone release was not responsible for the acute effects of indomethacin. No differences in plasma potassium were noted after indomethacin or vehicle infusion in the animals that underwent bilateral ureteral ligation, which suggests that indomethacin did not impair extrarenal potassium disposition. These results indicate that acute administration of indomethacin impairs the response to a potassium load, not as a result of inhibition of aldosterone secretion or extrarenal potassium distribution but by means of inhibition of renal potassium excretion.     

Oral triamterene disposition

Earlier studies of triamterene (T) disposition in man have reported hydroxytriamterene (T-OH) and hydroxytriamterene sulfate (T-O-SO3H) conjugate to be the major metabolites. We describe T kinetics through use of an HPLC method and confirm that after hydroxylation, T is rapidly converted to T-O-SO3H. The intermediate T-OH metabolite could not be detected in urine or plasma. Plasma concentrations of T-O-SO3H exceeded those of T by sevenfold to 26-fold, whereas concentrations of that metabolite in the urine were fourfold to thirteenfold higher than those of the parent. Renal clearance of T was 314.5 +/- 121.6 ml/min, exceeding that of the metabolite, which was 206.1 +/- 93.6 ml/min. Coadministration of hydrochlorothiazide increased urine flow and urinary pH, but it did not affect renal clearance of the parent drug or the metabolite. T bioavailability from capsules was poorer and more variable than that from a suspension. Hydrochlorothiazide did not influence the bioavailability of T.