Robert A. Upton

Bioavailability of Sublingual Buprenorphine

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron‐capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3‐ and 5‐minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2‐, 4‐, and 10‐minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two‐sided test. The 3‐ and 5‐ minute sublingual exposures each allowed 29 ± 10% bioavailability (area under the plasma concentration—time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2‐, 4‐, and 10‐minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.

Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine.

Buprenorphine and naloxone sublingual (s.l.) dose formulations may decrease parenteral buprenorphine abuse. We evaluated pharmacologic interactions between 8 mg s.l. buprenorphine combined with 0, 4, or 8 mg of naloxone in nine opiate-dependent volunteers stabilized on 8 mg s.l. buprenorphine for 7 days. Combined naloxone and buprenorphine did not diminish buprenorphines effects on opiate withdrawal nor alter buprenorphine bioavailability. Opiate addicts stabilized on buprenorphine showed no evidence of precipitated opiate withdrawal after s.l. buprenorphine-naloxone combinations. Buprenorphine and naloxone bioavailability was approximately 40 and 10%, respectively. Intravenous buprenorphine and naloxone produced subjective effects similar to those of s.l. buprenorphine and did not precipitate opiate withdrawal.

Buprenorphine Pharmacokinetics: Relative Bioavailability of Sublingual Tablet and Liquid Formulations

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM‐III‐R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration‐time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.

Pharmacokinetic Drug Interactions with Theophylline

Since up to 90% of a theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may be sufficient to necessitate adjustment of the theophylline dosage, preferably guided by plasma theophylline determinations.Comedication with phenobarbitone may require an increase of the theophylline dose by about 30% due to increased clearance resulting from enzyme induction. Similarly, with phenytoin and carbamazepine a dose increase of about 40 to 50% may be required. In the case of rifampicin, isoniazid or sulphinpyrazone comedication, an increase of the theophylline dose by about 20 to 25% may be needed.On the other hand, other drugs decrease theophylline clearance, making a reduction in the dose of concurrent theophylline advisable: with usual doses of erythromycin, propranolol and isoprenaline (isoproterenol), a reduction of about 25% is needed; with cimetidine and oral contraceptives by about 30% or more; and with triacetyloleandomycin (troleandomycin) by about 50%. In high doses, the xanthine oxidase inhibitor allopurinol can also retard theophylline elimination, and a reduction of the theophylline dose by about 20% may be advisable.Conflicting results have been reported on the influence of frusemide (furosemide) and influenza vaccines, while data regarding the effect of corticosteroids, benzodiazepines and verapamil on theophylline kinetics are not yet conclusive.Many drugs, however, appear not to significantly affect theophylline clearance. Some are from the same therapeutic group as the drugs mentioned above and offer clinical alternatives for coadministration with theophylline. Examples of drugs not found to have a significant effect on theophylline pharmacokinetics are ranitidine, josamycin, midecamycin, amoxycillin, tetracycline, cephalexin, cefaclor, orciprenaline, metoprolol, antacids, medroxyprogesterone acetate, metoclopramide and metronidazole.Most of the drugs discussed in this review appear not to affect the volume of distribution of theophylline significantly.

Pharmacokinetic Interactions Between Theophylline and Other Medication (Part II)

SummaryMany drugs have been found to increase or decrease the clearance of theophylline, probably by interaction with one or more of the variants of the cytochrome P450 drugmetabolising system. Theophylline may be particularly susceptible to alteration of its clearance because of the particular form(s) of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism. Its clearance has been found to be decreased (typically by around 25%, but often by far more) by erythromycin, troleandomycin (triacetyloleandomycin), roxithromycin, enoxacin, ciprofloxacin, Pefloxacin, norfloxacin, ofloxacin, fluoroquinolone T-3262, pipemidic acid, Cimetidine, etintidine, propranolol, verapamil, diltiazem, nifedipine, furosemide (frusemide), at least some anovulent agents, viloxazine, allopurinol, ticlopidine, idrocilamide, thiabendazole, disulfiram, influenza- and BCG-vaccination, interferon, and caffeine (half-life increase). In contrast, theophylline clearance (clearance/bioavailability) was found to be increased by isoprenaline (isoproterenol), terbutaline, some corticosteroids, Phenytoin, phenobarbital, activated charcoal, felodipine moricizine, benzodiazepines and sulfinpyrazone — typically by about 25%, but sometimes by as much as 80% or more. For several of these concomitant medications, however, only some of the published studies can substantiate an influence, which may highlight the sensitivity of some interactions to particular experimental and/or clinical conditions, e.g. with terbutaline, erythromycin, ciprofloxacin, norfloxacin, ofloxacin, phenobarbital. Cimetidine, verapamil, diltiazem, nifedipine, anovulents, allopurinol and influenza vaccination. Moreover, reports both of inhibition and of induction of theophylline clearance by each of rifampicin and isoniazid have appeared. Nevertheless, under investigation many medications have not been found to perceptibly influence theophylline disposition kinetics, e.g. ephedrine, orciprenaline (metaproterenol), prednisone, prednisolone, temelastine, terfenadine, mequitazine, pi-cumast, repirinast, josamycin, midecamycin, miocamycin, spiramycin, amoxicillin, am-picillin, cefalexin, cefaclor, Ceftibuten, cotrimoxazole (trimethoprim plus sulfamethoxazole), tetracycline, doxycycline, lomefloxacin, fluoroquinolones NY-198 and AM-833, nalidixic acid, lincomycin, metronidazole, certain antacids, ranitidine, roxatidine, piren-zepine, rioprostil, metoclopramide, meloprolol, atenolol, nadolol, medroxyprogesterone, dextropropoxyphene (propoxyphene). Piroxicam, ozagrel, mebendazole and ascorbic acid. Because theophylline has such a narrow therapeutic concentration range, changes in clearance of approximately 25% or more can have clinical impact. For patients requiring medication concomitant with theophylline, therefore, careful choices among alternative therapies, adjustment of the theophylline dosing regimen, and/or therapeutic drug monitoring may be advisable.

Methamphetamine and ethanol interactions in humans

Methamphetamine and ethanol are commonly used together. We examined the effects of intravenous methamphetamine (30 mg), oral ethanol (1 gm/kg), and the combination of methamphetamine (30 mg) and ethanol (1 gm/kg).

Convenient and sensitive high-performance liquid chromatography assay for ketoprofen, naproxen and other allied drugs in plasma or urine.

A new high-performance liquid chromatography technique enables convenient and rapid assay of ketoprofen and naproxen in biological samples at a sensitivity (10 and 2 ng/ml, respectively in plasma; 20 and 50 ng/ml in urine) far greater than previously available. Superior sensitivity is attributable to the buffered neutral eluent employed, which yields improved separation from material of biological origin. There is no interference from the major ketoprofen and naproxen metabolites tested and excellent reproducibility and accuracy can be maintained. Moreover, the same system can be used to assay probenecid and also shows promise of applicability to ibuprofen, fenoprofen and other members of the aryl-alkanoic acid class of non-steroidal anti-inflammatory agents.

Pharmacokinetics and Subjective Effects of Sublingual Buprenorphine, Alone or in Combination with Naloxone Lack of Dose Proportionality

AbstractObjective: Buprenorphine and buprenorphine/naloxone combinations are effective pharmacotherapies for opioid dependence, but doses are considerably greater than analgesic doses. Because dose-related buprenorphine opioid agonist effects may plateau at higher doses, we evaluated the pharmacokinetics and pharmacodynamics of expected therapeutic doses. Design: The first experiment examined a range of sublingual buprenorphine solution doses with an ascending dose design (n = 12). The second experiment examined a range of doses of sublingual buprenorphine/naloxone tablets along with one dose of buprenorphine alone tablets with a balanced crossover design (n = 8). Participants: Twenty nondependent, opioid-experienced volunteers. Methods: Subjects in the solution experiment received sublingual buprenorphine solution in single ascending doses of 4, 8, 16 and 32mg. Subjects in the tablet experiment received sublingual tablets combining buprenorphine 4, 8 and 16mg with naloxone at a 4: 1 ratio or buprenorphine 16mg alone, given as single doses. Plasma buprenorphine, norbuprenorphine and naloxone concentrations and pharmacodynamic effects were measured for 48–72 hours after administration. Results: Buprenorphine concentrations increased with dose, but not proportionally. Dose-adjusted areas under the concentration-time curve for buprenorphine 32mg solution, buprenorphine 16mg tablet and buprenorphine/naloxone 16/4mg tablet were only 54 ± 16%, 70 ± 25% and 72 ± 17%, respectively, of that of the 4mg dose of sublingual solution or tablet. No differences were found between dose strengths for most subjective and physiological effects. Pupil constriction at 48 hours after administration of solution did, however, increase with dose. Subjects reported greater intoxication with the 32mg solution dose, even though acceptability of the 4mg dose was greatest. Naloxone did not change the bioavailability or effects of the buprenorphine 16mg tablet. Conclusion: Less than dose-proportional increases in plasma buprenorphine concentrations may contribute to the observed plateau for most pharmacodynamic effects as the dose is increased.

Intraindividual variability in theophylline pharmacokinetics: Statistical verification in 39 of 60 healthy young adults

After administering a single 300 mg dose of theophylline in oral solution to 12 healthy adults, the dose-normalized area under the plasma concentration-time curve was 97.2±20.1 % (mean±SD) of that after giving a 500 mg dose and statistically indistinguishable. Similarly, these areas multiplied by the individuals terminal disposition rate constant (β) were statistically indistinguishable between 300 and 500mg doses (99.1±10.3%), giving no evidence of dose-dependence for theophylline kinetics at the levels below 15 μg/ml observed in these individuals. After an intravenous dose, a shortlived distribution phase (t1/2α) is sometimes seen. An a phase, however, is hardly discernible in over 250 profiles arising from oral doses administered during five single dose bioavailability studies. Almost all such profiles appear to follow single-compartment model predictions. With precautions to avoid a potential a phase, a terminal log-linear slope can be fitted by least squares analysis with a relative standard error in the slope determination almost always less than 6%. Covariance analysis confirms statistically that 39 of the 60 participating individuals varied in their β on the different occasions each was required to take a dose during the course of a crossover bioavailability trial. In one study, even though each individual was observed on only two occasions, 9 out of 12 showed statistically identifiable variation in β. Fluctuations in β of 60% can be seen. Changes of 30% or greater are common and can occur within 3 or 4 days. Thus real, large, and potentially frequent changes in β of theophylline have been identified in a majority of normal subjects. These changes do not appear to be confined to either sex, to smokers or nonsmokers, or to heavier or lighter individuals. No chronological pattern has, as yet, been recognized in the intraindividual variability in β.

Effects of probenecid on ketoprofen kinetics

When six normal men took probenecid with ketoprofen in a two‐treatment crossover study, steady‐state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 ± 7%, total ketoprofen clearance by 67 ± 11%, clearance of unbound ketoprofen by 74 ± 10%, clearance of unbound ketoprofen by conjugation by 91 ± 5%, and renal clearance of ketoprofen conjugates by 93 ± 4%. An apparent decrease (22 ± 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti‐inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large inter dose concentration swings of ketoprofen are then substantially reduced.