Comparative disposition of codeine and pholcodine in man after single oral doses.

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.

Pseudoephedrine and triprolidine in plasma and breast milk of nursing mothers.

Plasma and milk concentrations of pseudoephedrine and triprolidine were determined (by radioimmunoassay) in three lactating mothers over 12-48 h after ingestion of a combination medication containing 60 mg of pseudoephedrine hydrochloride and 2.5 mg of triprolidine hydrochloride monohydrate. Pseudoephedrine concentrations in milk were consistently higher than those in plasma. The total amount of drug in milk, as judged by areas under the respective curves (AUC), was two to three times greater than in plasma. Triprolidine concentrations in milk and plasma were more variable between subjects than those of pseudoephedrine. AUC values for milk and plasma were similar for one subject, while the plasma value exceeded that for milk in another woman. The fraction of the dose excreted in milk was estimated to be 0.4-0.7% for pseudoephedrine and 0.06-0.2% for triprolidine.

Triprolidine radioimmunoassay: disposition in animals and humans.

A hapten derivative of triprolidine, bearing an acrylic acid side chain ortho to the pyridine ring nitrogen atom, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with the resulting drug-protein conjugate resulted in the production of antisera capable of binding a radioiodinated tyramine conjugate of the triprolidine hapten derivative at high antiserum dilutions (1:70,000-1:150,000). These antisera were used to develop a radioimmunoassay (RIA) for triprolidine in human plasma with a sensitivity limit of 0.1 ng/mL (0.01 ng of actual mass). The known hydroxymethyl and carboxyl metabolites of triprolidine cross-reacted weakly (less than 2 and less than 0.05%, respectively) with this antiserum. The RIA could be used for the direct analysis of triprolidine in human and rabbit plasma, but not for rat or dog plasma, presumably due to the presence of other interfering substances (possibly metabolites). The validity of the RIA procedure in human plasma was demonstrated by comparative analysis of a number of samples by quantitative TLC (r = 0.985, slope = 1.076). The assay was employed to describe the pharmacokinetics of triprolidine in the rabbit (t 1/2, beta = 1.7 h). The assay had adequate sensitivity to detect low circulating drug concentrations in humans after therapeutic oral doses and also substantiated previous disposition experiments with triprolidine in humans (t 1/2, beta = 2.27 h). TLC analysis demonstrated that the absolute oral bioavailability of triprolidine (1-mg/kg dose) in the dog was low (4%). A comparison of triprolidine pharmacokinetic parameters in dogs, rabbits, rats, and humans revealed considerable similarity in elimination characteristics in these species.

Pharmacokinetics and O-dealkylation of morphine-3-alkyl ethers in the rat. A radioimmunoassay study.

Radioimmunoassay procedures were used to investigate the relationship between the chemical structure and disposition of morphine, codeine, ethylmorphine, t-butylmorphine, and pholcodine. Male Sprague-Dawley rats received po or iv doses of each drug equivalent to 10 mg/kg free base. Blood samples were collected at various times over the 6-hr period after each drug administration, and plasma concentrations of the parent drugs and metabolically produced morphine were determined. A single ethylmorphine antiserum was used for analysis of codeine, ethylmorphine, t-butylmorphine, and pholcodine in separate experiments, whereas a specific morphine antiserum was used in the radioimmunoassay of this compound. The absolute oral bioavailabilities of morphine, codeine, ethylmorphine, and t-butylmorphine all were below 10%, whereas that of pholcodine was over 40%. Terminal half-lives of morphine, codeine, ethylmorphine, and t-butylmorphine after iv administration all were less than 45 min, while that of pholcoline was over 2 hr. Codeine, ethylmorphine, t-butylmorphine, and pholcodine did not appear to undergo conjugation, as evidenced by the similarity between areas under the curve for total (unconjugated plus conjugated) and parent (unconjugated) drugs. Amounts of metabolically produced morphine in rats treated with codeine, ethylmorphine, t-butylmorphine, or pholcodine differed markedly. After oral administration, presystemic O-dealkylation of codeine and ethylmorphine was much greater than that of t-butylmorphine or pholcodine, presumably due to the presence of much bulkier 3-alkyl substituents in the latter compounds. Thus, the ratio of the morphine AUC to that of parent drug after po administration was 1.37 for codeine and 1.60 for ethylmorphine, but only 0.08 for t-butylmorphine and 0.01 for pholcodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Radioimmunoassay for bupropion in human plasma: comparison of tritiated and iodinated radioligands.

We evaluated the potential usefulness of 125I-labeled p-hydroxybupropion in a direct radioimmunoassay for bupropion in human plasma as compared with a currently used [3H]bupropion dextran-coated charcoal method. In both radioimmunoassay methods succinoylpropylbupropion antiserum was used that was highly specific for unchanged drug, cross reactivities with known bupropion metabolites being less than 0.3%. However, the use of 125I-labeled p-hydroxybupropion afforded greater sensitivity (0.3 microgram/L vs 0.6 microgram/L with [3H]bupropion) and was readily adaptable to the more convenient polyethylene glycol separation method. Between-assay CVs were 3.8 to 12.2% (mean 7.6%) with the 125I-based radioimmunoassay and 5.1 to 11.5% (mean 7.5%) with the 3H-based assay. Agreement between the two radioimmunoassay determinations of buproprion in human plasma samples collected over a 60-h period after oral drug administration was excellent (slope = 1.086, r = 0.989). We find the 125I-based assay a convenient and suitable alternative to the [3H]bupropion assay in pharmacokinetic studies in humans.

An evaluation of the effects of smoking on codeine pharmacokinetics and bioavailability in normal human volunteers.

Cigarette smoking has been shown to increase the clearance of several drugs, including pentazocine, theophylline, and phenacetin. This effect presumably is mediated through enzyme induction, resulting from inhaled polycyclic aromatic hydrocarbons. Because the O-demethylation pathway for codeine is similar to that of other drugs known to be influenced by cigarette smoking, a study was conducted to compare the pharmacokinetics and metabolism of codeine in smokers and nonsmokers. Twelve volunteers with no history of cigarette smoking and ten volunteers who smoke cigarettes were studied; an open, two-treatment, simultaneous parallel and crossover study design was used. Each volunteer received a single dose of codeine sulfate 60 mg po and codeine phosphate 60 mg im, in random treatment order, at one-week intervals. Serial blood samples were collected up to 12 hours after dosing, and plasma codeine and morphine concentrations were measured by radioimmunoassay. There was no significant difference between smokers and nonsmokers in either codeine or morphine areas under the plasma concentration-time curves (AUCs), with either route of administration. The relative codeine bioavailability in these groups was 54.8 +/- 4.9 percent and 50.2 +/- 2.1 percent (mean +/- SE), respectively. Smoking was associated with greater variability in plasma concentrations. Interestingly, greater morphine:codeine AUC ratios were observed in both groups after oral than after intramuscular administration. Cigarette smoking should have no clinically important influence on codeine absorption or disposition.

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

Relationships between immunogen structure and antisera specificity in the narcotic alkaloid series.

We report the production and comparative specificities of antisera raised to different immunogens containing codeine, morphine, and oxycodone. Antisera raised to bovine serum albumin (BSA) conjugates of codeine-6-hemisuccinate, ethylmorphine-6-hemisuccinate, or oxycodone-6-carboxymethyloxime had greatest recognition of structural changes around the piperidine ring nitrogen atom and th 14-position. N-carboxypropylnormorphine-BSA, N-carboxypropylnorcodeine-BSA, and norcodeine-BSA (directly coupled) conjugates elicited antisera that recognized structural changes at the 3- and 6-positions best, but also clearly discerned changes in the 14-substituent. Attachment of codeine to BSA via the 8-position gave a conjugate that elicited antisera with specificity characteristics similar to those of the antiserum to N-carboxypropylnorcodeine-BSA. Thus clear relationships existed between immunogen structure and antiserum specificity. The utility of these antisera was illustrated by the application of antiserum to codeine-6-hemisuccinate-BSA and solvent extraction to a study of codeine disposition in the dog. The specific antisera of N-carboxypropylnormorphine-BSA and to norcodeine-BSA were applied directly to an examination of the distribution of codeine and metabolically produced morphine in the milk and plasma of a nursing mother.

Radioimmunoassay and pharmacokinetic profile of bupropion in the dog.

A radioimmunoassay (RIA) procedure for the quantification of bupropion (dl-2-tert-butylamino-3'-chloropropiophenone) in biological fluids is described. Immunization of rabbits with conjugates of bovine serum albumin and p-succinoyl propylbupropion or p-carbomethoxybupropion resulted in the production of antisera which are capable of detecting less than 1 ng ml-1 (100 pg actual mass) of bupropion in the RIA, utilizing [6-3H] bupropion as radioligand. The antisera used in these studies have low cross-reaction (approximately 0.1% or less) with known side chain metabolites of bupropion, but exhibit significant cross-reaction with p-hydroxybupropion (30.3%). Excellent agreement was obtained between RIA and high-pressure liquid chromatography determinations of bupropion concentrations in human plasma samples, but plasma or serum from bupropion-treated dogs, rats and mice required extraction from basic medium to remove some interference before RIA. The assay was applied to a study of bupropion disposition in two beagles of each sex after i.v. and p.o. administrations of bupropion hydrochloride (100 mg). The pharmacokinetic profile in dogs was best described by an open two-compartment model after either route of drug administration. Peak plasma bupropion levels after oral dosing were highly variable, ranging from 12.9 to 63.5 ng ml-1 at 26 to 32 min after drug administration. The mean terminal phase half-life of bupropion was calculated to be 1.73 hr after either route and the absolute oral bioavailability of the drug varied from 2.0 to 6.5%.

Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects.

The pharmacokinetics of bupropion hydrochloride, a structurally novel antidepressant agent, have been studied in healthy male and female subjects following administration of single oral doses of 50, 100 and 200 mg. Plasma drug concentrations were determined directly by a specific radioimmunoassay (r.i.a.), while urinary measurements required a prior solvent extraction to remove substances interfering in the assay. Bupropion appeared rapidly in the plasma, suggesting good absorption. Drug plasma concentration-time data were fitted well to a two-compartment open model of drug disposition by use of the computer program NONLIN. By comparison of AUC, Cmax and tmax values, the pharmacokinetics of bupropion were found to be linear across the 50-200 mg dose range in both sexes. When the data were normalized for subjects' body weights, no differences between pharmacokinetic parameters for male and female subjects were found. Mean disposition half-lives across treatments were 1.2-1.4 h for t1/2 alpha and 10.7-13.8 h for the t1/2 beta. Bupropion was extensively bound (85%) to human plasma proteins over a wide drug concentration range. Less than 1% of a 200 mg oral dose of bupropion hydrochloride appeared in the urine of 16 subjects as unchanged drug, indicating extensive metabolism of the parent compound.

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Codeine kinetics as determined by radioimmunoassay.

Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 ng/ml) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 ng/ml) appeared within 0.75 to 1 hr. The mean plasma t1/2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5.1 L/kg, respectively. Oral, relative to intramuscular, bioavailability of codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).

Specific radioimmunoassays for codeine and morphine. Metabolism of codeine to morphine in the rat.

Specific antisera to morphine have been raised in response to immunization with a conjugate of N-carboxypropylnormorphine with bovine serum albumin (BSA). These antisera effectively distinguish changes in substituents at the 3 and 6 positions of the alkaloid, thus reducing cross-reactivity with codeine and morphine-3-glucuronide to negligible levels. The utility of these antisera has been illustrated by their application in radioimmunoassay procedures, along with similarly specific anti-codeine sera (Findlay et al., 1976) to a study of the biotransformation of codeine to morphine in the rat. After oral administration of codeine, serum levels of morphine were low, but significantly higher than codeine levels after 15 min., indicating rapid metabolism of codeine to morphine in this species.