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

Chen, ZR; Bochner, Felix; Somogyi, Andrew A.

doi:10.1111/j.1365-2125.1988.tb03404.x

Cited by 25 publications

(9 citation statements)

References 4 publications

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“…The inverse correlation between saliva pH and saliva codeine AUC is in keeping with the theoretical prediction based on the Henderson-Hasselbalch equation. Pholcodine, a drug with similar physicochemical properties to codeine, also has a high saliva to plasma concentration ratio (Chen et al, 1988b). The finding that the saliva codeine AUC during the dosing interval at steady state was higher than that after the single dose may be due to the difference (P = 0.05) in saliva pH between the two treatments, which averaged 6.6 and 6.4 after the single and chronic dose, respectively.…”

Section: Discussionmentioning

confidence: 98%

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

Chen

Somogyi

Reynolds

et al. 1991

Brit J Clinical Pharma

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116

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1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine‐6‐glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine‐6‐glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/‐ 0.31 h (mean +/‐ s.d.) and for codeine‐6‐glucuronide it was 1.28 +/‐ 0.49 h. The plasma AUC of codeine‐ 6‐glucuronide was 15.8 +/‐ 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/‐ 1.1 times higher than that in plasma. The elimination half‐life of codeine was 3.2 +/‐ 0.3 h and that of codeine‐6‐glucuronide was 3.2 +/‐ 0.9 h. 3. The renal clearance of codeine was 183 +/‐ 59 ml min‐1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine‐6‐glucuronide was 55 +/‐ 21 ml min‐1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine‐6‐glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine‐6‐glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/‐ 11.4% of the dose was recovered in urine, of which 59.8 +/‐ 10.3% was codeine‐6‐glucuronide, 7.1 +/‐ 1.1% was total morphine, 6.9 +/‐ 2.1% was total norcodeine and 11.8 +/‐ 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/‐ 31 ml min‐1 in the seven extensive metabolisers and 8 ml min‐1 in the poor metaboliser; to norcodeine the values were 103 +/‐ 33 ml min‐1 and 90 ml min‐1; to codeine‐6‐ glucuronide the values were 914 +/‐ 129 ml min‐1 and 971 ml min‐1; and intrinsic clearance was 1568 +/‐ 103 ml min‐1 and 1450 ml min‐1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionmentioning

confidence: 98%

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

Chen

Somogyi

Reynolds

et al. 1991

Brit J Clinical Pharma

Self Cite

116

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“…PHO is a mild cough suppressant acting directly on the cough center of the CNS, and it has become a widely used cough medicine in numerous formulations. Pharmacokinetically, it is much more slowly eliminated from the body than opioids like codeine, and the concentration in saliva becomes 3 to 4 times higher than in plasma,[3] properties that might add to its immunogenicity.…”

Section: Pholcodinementioning

confidence: 99%

The pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection

Florvaag

Johansson

2012

World Allergy Organization Journal

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The Scandinavian data on pholcodine (PHO) strongly indicates that there is a biological chain from PHO exposure through IgE-sensitization to IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBA). PHO is probably one of the strongest inducer of an IgE antibody response known. Of individuals taking PHO in cough medicines, over-the-counter accessibility to large populations, as many as 20 to 25% may become IgE sensitized. Once sensitized, PHO re-exposure will booster IgE antibody levels and IgE by around 100-fold. PHO is monovalent for 2 non-cross-reacting epitopes the quaternary ammonium ion (QAI), the main allergenic epitope of NMBA, and a non-QAI epitope. Thus, PHO most unlikely would initiate an allergic inflammatory response. Consequently, IgE sensitization is not revealed by obvious clinical signs, neither through tests based on IgE-sensitized effector cells. Therefore, it will escape detection if not assayed serologically. However, when subjected to general anesthesia, and thus the IgE-sensitized individual is administered a bivalent NMBA intravenously, the unrecognized presence of serum IgE antibodies to QAI may increase the risk of anaphylaxis 200- to 300-fold. Severe damages to patient's health can result, and mortality rates of 3 to 10% are reported. The Scandinavian experience indicates that the chain of events can efficiently be avoided by stopping PHO exposure: Within 1 year, the prevalence of IgE sensitization to PHO and QAI decreases significantly, and after 2 to 3 years, the numbers of reported anaphylactic reactions decreases equally so.

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“…After taking a dose of 90 rag, about 200 ng/mL of methadone is detectable in saliva 24 h later (45) ( Table II). Likewise, pholcodine, a synthetic opioid widely used as an antitussive drug has been determined in saliva and compared with plasma and urine levels (46,47). Good correlation between the three media was reported (r> 0.99) with concentrations in saliva about four times greater than in plasma (46) ( Table III).…”

Section: Opioidsmentioning

confidence: 99%

Drugs of Abuse in Saliva: A Review

Schramm¹,

Smith²,

Craig³

et al. 1992

Journal of Analytical Toxicology

174

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There has been substantial interest in the use of saliva as a diagnostic medium for drugs of abuse because it can be obtained noninvasively. Although drugs of abuse have been investigated in saliva for more than a decade, the role of saliva remains uncertain. A clear picture is difficult to obtain because of variations in (1) the analytical methods used; (2) the dose regimen of subjects, which was either unknown or differed between studies; and (3) the elapsed time between drug intake and sample collection. This communication summarizes the studies on the quantitative determination of different drugs of abuse in saliva to elucidate the current status in this area. Marijuana, cocaine, phencyclidine, opiates, barbiturates, amphetamines, and diazepines (or their metabolites) have all been detected in saliva by various analytical methods, including immunoassay, gas chromatography/mass spectrometry, and thin layer chromatography. Initial studies with cocaine and phencyclidine suggest a correlation between saliva and plasma concentrations of these drugs, indicating a dynamic equilibrium between saliva and blood. Tetrahydrocannabinol, the active component in marijuana, on the other hand, does not appear to be transferred from plasma to saliva. However, tetrahydrocannabinol is sequestered in the buccal cavity during smoking and can be detected in saliva. These findings point to the potential role of saliva in the analysis of many illicit drugs. To clearly identify the role of saliva as a diagnostic medium for drugs of abuse, research efforts should be directed towards (1) performing systematic studies on correlations between saliva, blood, and urine and (2) determining the concentrations of drugs and their metabolites in saliva as a function of dose and time after intake.

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

Cited by 25 publications

References 4 publications

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

The pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection

Drugs of Abuse in Saliva: A Review

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