Influence of Plasma-protein Binding on Analgesic Effect of Methadone in Rats with Spontaneous Withdrawal

Garrido, María J.; Jiminez, R.; Tamayo, Eduardo; Calvo, Rosario

doi:10.1111/j.2042-7158.1996.tb05917.x

Cited by 20 publications

(7 citation statements)

References 17 publications

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“…Thus, heroin addicts who show objective signs of opiate withdrawal tend to have elevated plasma levels of α 1 ‐acid glycoprotein and increased ex vivo plasma binding of methadone compared with normal subjects [ 44]. Similarly, increased plasma binding of methadone has been observed in rats with withdrawal effects immediately after chronic heroin administration [ 45]. Hence, it may be postulated that substitution of heroin with methadone and suppression of opiate withdrawal symptoms is accompanied by a decrease in the level of α 1 ‐acid glycoprotein and of methadone binding.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changes

Rostami‐Hodjegan

Wolff

Hay

et al. 1999

Brit J Clinical Pharma

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Aims Although methadone is widely used to treat opiate dependence, guidelines for its dosage are poorly defined. There is increasing evidence to suggest that a strategy based on plasma drug monitoring may be useful to detect non-compliance. Therefore, we have developed a population-based pharmacokinetic (POP-PK) model that characterises adaptive changes in methadone kinetics. Methods Sparse plasma rac-methadone concentrations measured in 35 opiate-users were assessed using the P-Pharm software. The final structural model comprised a biexponential function with first-order input and allowance for time-dependent change in both clearance (CL) and initial volume of distribution ( V ). Values of these parameters were allowed to increase or decrease exponentially to an asymptotic value. Results Increase in individual values of CL and increase or decrease in individual values of V with time was observed in applying the model to the experimental data. Conclusions A time-dependent increase in the clearance of methadone is consistent with auto-induction of CYP3A4, the enzyme responsible for much of the metabolism of the drug. The changes in V with time might reflect both up-and downregulation of a 1 -acid glycoprotein, the major plasma binding site for methadone. By accounting for adaptive kinetic changes, the POP-PK model provides an improved basis for forecasting plasma methadone concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate-users on maintenance treatment.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changes

Rostami‐Hodjegan

Wolff

Hay

et al. 1999

Brit J Clinical Pharma

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“…A study in opiate-tolerant rats [41] has shown that enforced abstinence is associated with an increase in a 1 -acid glycoprotein, a major binding site for methadone in plasma [39]. Furthermore, opiate users about to begin a programme of methadone treatment are reported to have elevated plasma concentrations of this protein (1.22±0.10 s.d.…”

Section: Pharmacokineticsmentioning

confidence: 99%

The pharmacokinetics of methadone in healthy subjects and opiate users

Wolff¹,

Rostami‐Hodjegan

Shires

et al. 1997

Brit J Clinical Pharma

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Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

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“…(16) reported that the signs of spontaneous morphine withdrawal consisted of teeth‐chattering, mastication, wet‐dog shakes, yawning, forepaw tremors, ptosis, eye twitching, piloerection and diarrhoea. Withdrawal lasted for 84 h, with the most severe manifestation of signs occurring at 36 h. In a similar study, adult rats became physically dependent within 3 weeks on morphine added to their drinking water (17). Withdrawal throughout a 72‐h period consisted of posturing, vocalization on touch, ptosis, diarrhoea, rearing, jumping, wet‐dog shakes and teeth chattering, with the most severe manifestation of signs occurring at 24 h. Therefore, in both infant and adult rats spontaneous morphine withdrawal lasts for approximately 72 h, with the most severe manifestation of signs occurring from 24 to 48 h.…”

Section: Comparison Of Spontaneous Morphine Withdrawal Between Infantmentioning

confidence: 97%

Buprenorphine blocks withdrawal in morphine‐dependent rat pups

Stoller

Smith

2004

Pediatric Anesthesia

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Influence of Plasma-protein Binding on Analgesic Effect of Methadone in Rats with Spontaneous Withdrawal

Cited by 20 publications

References 17 publications

Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changes

Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changes

The pharmacokinetics of methadone in healthy subjects and opiate users

Buprenorphine blocks withdrawal in morphine‐dependent rat pups

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