CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement.

The individual cytochrome P450 isoforms in dextropropoxyphene N-demethylation to nordextropropoxyphene were determined and the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized. Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively. Nordextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (Km = 179 +/- 74 microM, Cl(int) = 0.41 +/- 0.26 ml mg(-1)h(-1)) and the PM subject (K = 225 microM, Cl(int) = 0.19 ml mg(-1) h(-1)) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in CYP2D6 EM and PM subjects. CYP3A4 is the major CYP enzyme catalysing the major metabolic pathway of dextropropoxyphene metabolism. Hence variability in the pharmacodynamic effects of dextropropoxyphene are likely due to intersubject variability in hepatic CYP3A4 expression and/or drug-drug interactions. Reported CYP2D6 phenocopying is not due to dextropropoxyphene being a CYP2D6 substrate.

The relationship between mood state and plasma methadone concentration in maintenance patients.

Although methadone maintenance is designed to stabilize opioid-dependent patients, some experience significant withdrawal in the latter part of the 24-hour interdosing interval. This study was designed to determine the mood changes that maybe associated with such withdrawal. Eighteen methadone patients, nine of whom experienced significant withdrawal, were tested over a single interdosing interval. During this time, 13 blood samples were collected to measure plasma racemic methadone concentrations, and the Profile of Mood States (POMS) was administered on 11 of these occasions. The POMS was also administered on 11 occasions over 24 hours to 10 drug-free healthy controls. In comparison with controls, methadone patients showed increased anger, depression, tension, confusion, and fatigue, as well as decreased vigor. For all scales, maximal differences from controls occurred at times of trough methadone concentration and minimal differences around the time of peak concentration. Changes in mood over the interdosing interval were more exaggerated in the nine patients who experienced significant withdrawal compared with those who did not. The composite Total Mood Disturbance (TMD) scores were calculated for each subject at each time point. The sigmoid Emax model was used to relate plasma concentrations to these data and to calculate the slope factor (N). This model could be fitted for 14 of the 18 patients with a mean +/- SEM slope factor of 2.2 +/- 0.5. TMD score was also shown to be inversely related to the rate of decline in methadone concentration from peak to trough. These results show that significant mood changes occur in response to changes in methadone concentration, and these are more pronounced in those who experience withdrawal. The concentration-effect relationships suggest that relatively small changes in plasma concentration will result in significant mood change. Differences in the degree of mood change between those who do and do not experience significant withdrawal may be explained by variation in the rate of decline in plasma concentration from peak to trough.

Simultaneous quantification of amoxycillin and metronidazole in plasma using high-performance liquid chromatography with photodiode array detection.

A simple, robust HPLC method was developed to measure simultaneously the plasma concentrations of amoxycillin and metronidazole in order to assess their disposition in the eradication of Helicobacter pylori. Plasma samples were protein precipitated, pH adjusted and the supernatant injected onto the HPLC system which used a C18 column, paired-ion aqueous mobile phase and photodiode array detection of amoxycillin at 230 nm and metronidazole at 313 nm. Intra- and inter-day precision and inaccuracy were less than 10% for concentrations between 5 and 20 mg/l. The limit of quantification was 1 mg/l. Samples were stable on the HPLC injector for 48 h at room temperature and multiple freeze-thaw cycles led to no decomposition.

Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships.

OBJECTIVE: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity. METHODS: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid Emax model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated. RESULTS: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h). CONCLUSIONS: In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.