Comparative biotransformation of morphine,codeine and pholcodine in rat hepatocytes: identification of a novel metabolite of pholcodine

1. Pholcodine (3-morpholinoethylmorphine), a semi-synthetic alkaloid, is widely used as an antitussive agent. 2. Norpholcodine [7,8-didehydro-4,5 α -epoxy-3-(2-morpholinoethoxy)morphinan-6 α -ol] (NP) and pholcodine-N-oxide [1(9a)-dehydro-(4aR,5S,7a R,9c S,12S)-4a,5,7a,8,9,9a-hexahydro-5-hydroxy-12-methyl-3-morpholinoethoxy-1 H -8,9,c-(iminoethano)phenanthro[4,5-bcd] furan-12-oxide] (PNOX) were identified in incubations of pholcodine with freshly isolated rat hepatocytes by liquid chromatography/electrospray-mass spectrometry (LC/ESI-MS). 3. Synthesized NP and PNOX were characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. 4. N -oxidation was the major metabolic pathway for pholcodine, producing a previously unreported metabolite. 5. The metabolism of morphine and codeine was also determined using freshly isolated hepatocytes. 6. For morphine, 3-glucuronidation was the major metabolic pathway, whilst for codeine it was dealkylation (O - and N -). 7. Neither morphine nor its metabolites were metabolites of pholcodine. 8. This observation supports the hypothesis that the absence of analgesic activity with pholcodine may be due to less O -dealkylation in vivo. 9. Together with the slow biotransformation of pholcodine (k met = 0.021 µM?min -1) in comparison with morphine (k met = 0.057 µM?min -1) and codeine (k met = 0.112 µM?min -1), the results obtained were consistent with its low addiction potential and suggest that its antitussive efficacy is mediated by the parent drug or one of its metabolites other than morphine.     

Metabolism of pholcodine in man

This paper describes studies on the metabolism of the antitussive 3-O-(-2'-morpholinoethyl)-morphine (pholcodine, Tussokon) in man. The metabolites were identified after cleavage of conjugates, extraction and derivatization by acetylation in human urine using gas chromatography-mass spectrometry. The following seven metabolites could be identified besides the unchanged pholcodine (P): Nor-P, desmorpholino-hydroxy-P, nor-desmorpholino-hydroxy-P, hydroxy-P, oxo-P, nor-oxo-P and morphine in traces. Therefore, the following four partly overlapping phase I metabolic pathways can be postulated: N-demethylation, N-desalkylation at the morpholino ring followed by reduction of the resulting aldehyde to the desmorpholino-hydroxy metabolite, oxidation of the morpholino ring to the hydroxy and oxo metabolite, and O-desalkylation to morphine. With the exception of morphine, pholcodine and its phase I metabolites were not converted to enzyme-hydrolysable conjugates. Pholcodine itself could be detected in urine 5-7 weeks after ingestion, the desmorpholino-hydroxy metabolite 1-2 weeks and the other metabolites only in the first few hours. It can be concluded that the low metabolism of the rather lipophilic pholcodine is the reason for the very slow elimination.     

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.     

Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents

We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).     

Multiple carriers for uptake of [3H]estradiol-17 beta(beta-D-glucuronide) in isolated rat hepatocytes

The transport of the cholestatic steroid glucuronide, 3H-estradiol-17 beta-(beta-D-glucuronide) (E2 17G), was examined in isolated female rat hepatocytes over a broad substrate concentration range (0.1-100 microM). Two different carrier systems were identified with the following kinetic parameters: Km1 = 4.54 microM; Vmax1 = 0.149 nmol/min/mg protein; Km2 = 149 microM; Vmax2 = 0.641 nmol/min/mg protein. Taurocholate and testosterone glucuronide selectively and competitively inhibited [3H]-E2 17G uptake at the high affinity site. Ki values calculated for taurocholate (43 microM) and testosterone glucuronide (28 microM) indicated that these two inhibitors were relatively weak competitors for this E2 17G transport site. Conversely, E2 17G inhibited [3H]taurocholate uptake into isolated hepatocytes (Ki = 43 microM). Bromosulfophthalein (10 microM) inhibited uptake of 0.5-50 microM [3H]-E2 17G by 55-85%, whereas morphine glucuronide (100 microM) had no significant effect on uptake of [3H]-E2 17G at these concentrations. The effects of taurocholate, testosterone glucuronide, bromosulfophthalein, and morphine glucuronide on [3H]-E2 17G uptake into isolated rat hepatocytes correlated with the ability of these agents to inhibit binding of [3H]-E2 17G to specific sites in rat liver plasma membranes. These data support the postulate that the two [3H]-E2 17G binding sites identified in female rat liver plasma membranes represent two distinct organic anion carriers and indicate that the high affinity site for [3H]-E2 17G represents a carrier that is shared by organic anions and bile acids.     

The antitussive activity of a novel compound RU 20201

A novel compound, 1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one dihydrochloride (RU 20201), has been shown to have comparable antitussive activity to that of codeine phosphate in animal experiments after oral administration. RU 20201 was also shown to have local antitussive activity when given by aerosol. This effect took place immediately. Initial observations suggest that RU 20201 is an antitussive compound that exerts its activity in the lungs, probably by direct inhibition of superficial receptors in the respiratory tract.     

Antitussive effect of RU-20201--central and peripheral actions

The antitussive effect of the new compound 1, 2, 3, 4a, 9b-hexahydro-8, 9b-dimethyl-4-[3-(4-methyl-piperazine-1-yl) propionamide] dibenzofuran-3-one dihydrochloride (RU-20201) was investigated in dogs and guinea pigs, including its sites of action. The antitussive effect of RU-20201 was about 1/10 as potent as that of codeine phosphate in dogs with the puncture electrode-induced cough (PEC) method and about 1/12 and 1/4 as potent as that of codeine phosphate in guinea pigs with the PEC and chemical stimulation methods, respectively. When RU-20201 was administered in a dose range of 1 to 10 mg into the vertebral artery toward the brain in lightly anesthetized dogs, no antitussive effect was observed against the coughing elicited by electrical stimulation of the central cut end of the superior laryngeal nerve. However, a stimulative effect on respiration, especially on respiratory rate occurred. The peripheral effect of RU-20201 on the cough was investigated using the in situ upper trachea perfusion preparation which allows a direct drug administration to the local site around the tracheal mucosa, this site being electrically stimulated to induce coughing. A close i.a. infusion of RU-20201 in doses of 1 and 3 mg/min into the tracheal vascular bed for 5 min inhibited the cough response elicited by mucosal stimulation. The above findings suggest that RU-20201 has a significant antitussive activity, the site of action being probably, at least, at the cough receptor level.     

Urinary concentrations of codeine and morphine after the administration of different codeine preparations in relation to doping analysis.

A capillary GC method with nitrogen-specific detection is described for the analysis of codeine and morphine in urine. Both drugs were determined after enzymatic hydrolysis of the urine. Morphine was derivatized with trifluoroacetic anhydride. For 5-ml samples of urine, the lower detection limits for accurate quantitation were 50 ng ml-1 and 100 ng ml-1 for morphine and codeine, respectively. Both codeine and morphine were already detectable in urine 1 h after the intake of the analgesic preparation Perdolan. Codeine excretion and concentration peaked 2 h after administration of a dose. The percentage of the dose excreted as codeine was 3.0-6.2%. Administration of the antitussive preparation Bisolvon Griblettes resulted in detectable codeine and morphine levels for at least one day; 5.6-9% was excreted as total codeine over 24 h, the conjugated metabolite morphine accounting for 1.7-7.4% of the dose. Nearly the same amounts of codeine and morphine were excreted after administration of the antitussive syrup Bronchodine. The maximum excretion rate of codeine occurred after 1 h. Generally codeine and morphine remained detectable for 12 h. The results of these administration studies are discussed in relation to the codeine and morphine threshold levels recently introduced by the International Cyclist Union.     

Metabolism of 1-[14C]nitropyrene in respiratory tract tissue of rats exposed to diesel exhaust

The purpose of this study was to determine how prior exposure of rats to graded concentrations of diesel exhaust would affect respiratory tract tissue metabolism of 1-nitropyrene (NP), a known constituent of diesel exhaust. Rats were exposed (whole body) 7 hr/day, 5 days/week for 4 weeks to clean air (controls) or to diluted diesel exhaust containing concentrations of 350, 3300, and 7400 micrograms particles/m3. After exposures, nasal tissue and lungs from rats were tested for their ability to metabolize NP. Rat nasal tissue was incubated for 10 min with 20 microM 1-[14C]NP. Isolated perfused rat lungs were perfused for 90 min with 25 microM 1-[14C]NP. NP metabolites formed in rat nasal tissue and the isolated perfused rat lung were separated by high-pressure liquid chromatography. Exposure of rats to 7400 micrograms particles/m3 for 4 weeks resulted in significant increases (twofold) in rates of NP metabolism in both nasal tissue (440 pmol/mg protein/min) and the isolated perfused rat lung (112 nmol/g lung). Exposure of rats to lower concentrations of diesel exhaust did not increase the rates of NP metabolism in either rat nasal tissue or perfused rat lungs. In all cases, the major metabolites of NP formed in nasal tissue and perfused lungs were 3-, 6-, and 8-hydroxy-1-nitropyrene and 4,5-dihydro-4,5-dihydroxy-1-nitropyrene. A fourfold increase was observed in the amounts of 14C covalently bound in lungs from rats exposed to 7400 micrograms particles/m3. The results from this study indicate that exposure to diesel exhaust particles significantly alters metabolism and subsequent covalent binding of NP.     

Inward transport of [3H]-1-methyl-4-phenylpyridinium in rat isolated hepatocytes: putative involvement of a P-glycoprotein transporter.

1. The liver has an important role in the detoxification of organic cations from the circulation. [3H]-1-methyl-4-phenylpyridinium ([3H]-MPP+), a low molecular weight organic cation, is efficiently taken up and accumulated by rat hepatocytes through mechanisms partially unknown. 2. The aim of the present work was to characterize further the uptake of MPP+ by rat isolated hepatocytes. The putative interactions of a wide range of drugs, including inhibitors/substrates of P-glycoprotein, were studied. 3. The uptake of MPP+ was investigated in rat freshly isolated hepatocytes (incubated in Krebs-Henseleit medium with 200 nM [3H]-MPP+ for 5 min) and in the rat liver in situ (perfused with Krebs-Henseleit/BSA medium with 200 nM [3H]-MPP+ for 30 min). [3H]-MPP+ accumulation in the cells and in tissue was determined by liquid scintillation counting. 4. Verapamil (100 microM), quinidine (100 microM), amiloride (1 mM), (+)-tubocurarine (100 microM), vecuronium (45 microM), bilirubin (200 microM), progesterone (200 microM), daunomycin (100 microM), vinblastine (100 microM), cyclosporin A (100 microM) and cimetidine (100 microM) had a significant inhibitory effect on the accumulation of [3H]-MPP+ in isolated hepatocytes. Tetraethylammonium (100 microM) had no effect. 5. In the rat perfused liver, both cyclosporin A (100 microM) and verapamil (100 microM) had much less marked inhibitory effects as compared to their effects on isolated hepatocytes (0% against 35% and 45% against 96% of inhibition, respectively). 6. Inhibition of alkaline phosphatase activity by increasing or decreasing the pH of the incubation medium or by the presence of vanadate (1 mM) or homoarginine (500 microM) led to a significant increase in the accumulation of [3H]-MPP+ in isolated hepatocytes. 7. It was concluded that, in addition to the type I organic cation hepatic transporter, [3H]-MPP+ is taken up by rat hepatocytes through P-glycoprotein, a canalicular transport system that usually excretes endobiotics and xenobiotics. We proposed that the reversal of transport through P-glycoprotein may be related to the loss of efficacy of alkaline in isolated hepatocytes.     

Synthesis and antitussive activity of 3-azabicyclo[3.2.2]nonane derivatives

Mannich bases derived from a number of substituted acetophenones and propiophenones and 3-azabicyclo[3.2.2]nonane have been evaluated for antitussive activity. One of these compounds was as potent as codeine and dextromethorphan in its antitussive activity. The most potent compound of the series, 3-(3-azabicyclo[2.2.2]nonan-3-yl)-4'-benzyloxy-2-methyl propiophenone, also exhibited antimorphine activity. There was no direct correlation between the antitussive effect and antimorphine activity.     

In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay.

The effects of hepatic uptake and efflux transporters on erythromycin (ERY) disposition and metabolism were examined by comparing results from rat hepatic microsomes, freshly isolated hepatocytes, and in vivo studies. Uptake studies carried out in freshly isolated rat hepatocytes showed that ERY and its metabolite (N-demethyl-ERY) are substrates of Oatp1a4 and Oatp1b2. Whereas rifampin and GG918 [GF120918: N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine] exerted minimal effects on metabolism in microsomes, rifampin (2.5 microM) and GG918 (0.5 microM) significantly decreased and increased ERY metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the intracellular N-demethyl-ERY control area under the curve (AUC) (0.795 +/- 0.057 microM . min), a decreased AUC (0.513 +/- 0.028 microM . min, p < 0.005) was observed when ERY was coincubated with rifampin, and an increased AUC (2.14 +/- 0.21 microM . min, p < 0.05) was found when GG918 was present. The results of the i.v. bolus studies showed that, compared with the ERY clearance of the controls (47.2 +/- 12.5 ml/min/kg for the rifampin group and 42.1 +/- 5.7 for the GG918 group), a decreased blood clearance, 29.8 +/- 6.1 ml/min/kg (p < 0.05) and 21.7 +/- 9.0 ml/min/kg (p < 0.01), was observed when rifampin or GG918, respectively, was coadministered. When either inhibitor was codosed with ERY, volume of distribution at steady state was unchanged, but t1/2 and mean residence time significantly increased compared with the controls. Hepatic uptake and efflux transporters modulate intracellular concentrations of ERY, thereby affecting metabolism. The interplay of transporters and enzymes must be considered in evaluating potential drug-drug interactions.     

Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.

1. Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.D-Arg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guinea-pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression. 2. Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-1 s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-1, i.v. The antitussive effects of subcutaneous codeine (25 mg kg-1) morphine (8.1 mg kg-1) and BW443C (2.5 mg kg-1) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-1) and N-methylnalorphine (3.0 mg kg-1). 3. In the multiple toe-pinch test, the antinociceptive ED50s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-1, s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg-1) antagonized the antinociceptive action of codeine (25 mg kg-1) and morphine (8.1 mg kg-1). In contrast, N-methylnalorphine (3.0 mg kg-1) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

The general pharmacology of a novel antitussive compound RU 20201.

1,2,3,4,4a,9b-Hexahydro-8,9b-dimethyl-4[3-(4-methyl piperazin-1-yl)propionamido] dibenzofuran-3-one dihydrochloride (RU 20201) is an antitussive compound with a potency comparable to that of codeine. Unlike codeine, RU 20201 is devoid of any apparent CNS effects and does not depress the respiratory system. It has no adverse effect on the gastrointestinal tract no has it any analgesic or anti-inflammatory properties. Only at very high doses was a local anaesthetic effect observed.     

Potentiation of antitussive effect of codeine by some 1-dimethoxyphenyl-3-alkylaminobutanols in guinea pigs

Newly synthesized 1-(2',5'-dimethoxyphenyl)-1-n-butyl-3-diethylaminobutanol (compd. 4) and its analogs enhanced the antitussive effect of codeine and morphine as tested on the cough induced by mechanical stimulation of the trachea in guinea pigs. This effect was illustrated to be a potentiation on the Gaddum's diagram. The following parameters were affected little or to a small extent: 1. analgesic effect of codeine and morphine in guinea pigs and mice, 2. duration of anesthesia induced by hexobarbital in mice, 3. respiratory depression caused by codeine in guinea pigs, and 4. LD50 of codeine in guinea pigs and mice. Explorations of the mechanism of potentiating action suggested some peripheral mechanism, but the exact one remained to be elucidated.     

Induction of epoxide hydrolase in cultured rat hepatocytes and hepatoma cell lines

The expression of epoxide hydrolases was studied in cultured rat hepatocytes and hepatoma cell lines. Styrene 7,8-oxide and benzo[a]pyrene 4,5-oxide were used as substrates for microsomal epoxide hydrolase and trans-stilbene oxide for the cytosolic form of this enzyme. In freshly isolated hepatocytes from control rats, microsomal epoxide hydrolase activity was 7.7 and 10.8 nmoles/mg cellular protein/min with benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide as substrates respectively. This enzyme activity increased by more than 2-fold in hepatocytes after 24 hr in culture and remained elevated throughout 96 hr using both substrates. In cultured hepatocytes from rats pretreated in vivo with phenobarbital, trans-stilbene oxide, 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene, both benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide hydrolase activities were increased greater than 1.8 relative to controls. Hepatocytes from 2-acetylaminofluorene-pretreated animals at 24 hr in culture had approximately 9-fold higher activities than control hepatocytes. In marked contrast to microsomal epoxide hydrolase activity, the cytosolic enzyme showed an initial activity of 191 pmoles/mg cellular protein/min in freshly isolated hepatocytes, decreased by 75% after 24 hr in culture, and was barely detectable at 96 hr. A similar trend was apparent in hepatocytes from the pretreated animals. In vitro treatment of hepatocytes with trans-stilbene oxide and phenobarbital increased microsomal epoxide hydrolase, while this activity was refractory to 2-acetylaminofluorene treatment. Styrene 7,8-oxide hydrolase activity was increased in the McA-RH-7777 rat hepatoma cell line by phenobarbital, trans-stilbene oxide and 2-acetylaminofluorene treatment. Similarly, benzo[a]pyrene 4,5-oxide hydrolase activity was also increased in this cell line by treatment with phenobarbital and trans-stilbene oxide but not by 2-acetylaminofluorene. Microsomal epoxide hydrolase activity in rat H4-II-E hepatoma cells was refractory to induction, except by trans-stilbene oxide treatment, which caused a 70% increase in benzo[a]pyrene 4,5-oxide hydrolase activity.     

Evidence for peripheral mechanisms mediating the antitussive actions of opioids in the guinea pig.

1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting mu-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs. 2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively. 3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were approximately 2.2 and approximately 12 micrograms/kg, respectively. 4. Aerosilized codeine (approximately 72 micrograms/kg, n = 5) significantly inhibited coughing by 62 +/- 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 +/- 6%, n = 7). 5. Inhalation of DALDA (approximately 7.2 micrograms/kg, n = 7) also significantly inhibited coughing. 6. The antitussive effect of inhaled morphine (approximately 7.2 micrograms/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally. 7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.     

Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.

1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration.     

托吡酯的合成工艺改进

本研究发现在托吡酯(1)的合成过程中可生成杂质[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[[1,3]二氧戊环]-并[4,5-b:4',5'-d]吡喃-3a-基]甲基[(3aS,5aS,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[[1,3]二氧杂戊环]并[4,5-b:4',5'-d]吡喃-3a-基)甲基]氨基磺酸酯(4),其结构经核磁和质谱鉴定确证,证明4是由油状物2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖氯磺酸酯(2)中残余的2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖苷(3)与1反应引起。因此,对2合成工艺进行了改进。将3与磺酰氯在二氯甲烷/甲苯混合溶剂中反应得油状物2,经异丙醚精制首次制得固体2,其中3的含量降至0.05%。将固体2与氨气反应得1,产品无需精制,纯度99.93%,总收率87%(以3计)。该工艺易于除去杂质,所得中间体2为固体,存储取样方便。     

Oral administration of codeine in the presence of ethanol: a pharmacokinetic study in man

Three healthy male volunteers were given a codeine (1 mg/kg) solution in the absence and presence of ethanol in a cross-over designed study. The blood ethanol concentration was kept at approximately 16 mM for 8 hrs. Blood samples were taken at several occasions during the first day after the codeine administration. Urine was sampled during three days. There were no significant differences in the area under serum concentration versus time curve in the absence and presence of ethanol with respect to free codeine, total codeine and total morphine. The fraction of codeine glucuronized in serum (approximately 94%), the maximum serum concentration of free (0.34 microM) and total codeine (6.3 microM), the time to reach the maximum serum concentration values (approximately 65 min.) were also similar in the absence and presence of ethanol. The accumulated percentage of the codeine dose given which was found as codeine and morphine and their conjugates in the urine ranged from 50 to 91 percent in the different subjects. The accumulated percentage of the administered codeine dose found as free morphine in the urine, was significantly lower in the ethanol exposed individuals (0.18 +/- 0.03%) compared to the controls (0.39 +/- 0.09%). The percentage of the codeine dose found in the urine in the control situation as free codeine (5.2 +/- 2.2%) was not statistically different from the amount found in the urine after ethanol treatment (4.3 +/- 2.0%). The percentage glucuronized morphine (95.3 +/- 0.4%) and codeine (91.9 +/- 2.2%) in the urine in the absence of ethanol was similar to glucuronized morphine (95.3 +/- 2%) and codeine (93.1 +/- 3%) after ethanol exposure.(ABSTRACT TRUNCATED AT 250 WORDS)