The effect of intravenous sulfobutylether7 -ß-cyclodextrin on the pharmacokinetics of a series of adamantane-containing compounds.

Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.v. pharmacokinetic profile of a drug is unchanged in the presence of CD. The altered pharmacokinetics of a synthetic ozonide in rats has been attributed to an unusually high-binding affinity (2.3 × 10(6) M(-1) ) between the drug and sulfobutylether7 -ß-cyclodextrin (SBE7 -ß-CD) with further studies suggesting a significant binding contribution from the adamantane ring. This work investigated the binding affinity of three adamantane derivatives [amantadine (AMA), memantine (MEM) and rimantadine (RIM)] to SBE7 -ß-CD and the impact of complexation on their i.v. pharmacokinetics. In vitro studies defined the plasma protein binding, as well as the impact of SBE7 -ß-CD on erythrocyte partitioning of each compound. SBE7 -ß-CD binding constants for the compounds were within the typical range for drug-like molecules (10(2) -10(4) M(-1) ). The pharmacokinetics of AMA and MEM were unchanged; however, significant alteration of RIM plasma and urinary pharmacokinetics was observed when formulated with CD. In vitro studies suggested two factors contributing to the altered pharmacokinetics: (1) low plasma protein binding of RIM, and (2) decreased erythrocyte partitioning in the presence of high SBE7 -ß-CD concentrations. This work demonstrated the potential for typical drug-cyclodextrin interactions to alter drug plasma pharmacokinetics.

High-performance liquid chromatographic determination of memantine in human urine following solid-phase extraction and precolumn derivatization.

A validated HPLC-UV method is presented for the quantification of urinary memantine hydrochloride, a novel medication approved to treat moderate and advanced cases of Alzheimer's disease. The drug and amantadine hydrochloride, the internal standard, were extracted from human urine using SPE. The extract was then buffered and derivatized at room temperature using o-phthalaldehyde in the presence of N-acetyl-L-cyteine. Chromatographic separation of the formed derivatives was achieved on a C18 column using methanol-water mobile phase adjusted to pH 7 and pumped isocratically at 1 mL/min. The UV detector was set at 340 nm. The chromatographic run time did not exceed 10 min. The LOD and LOQ were 8 and 20 ng/mL, respectively. The RSDs for intraday and interday precisions did not exceed 5.5%. The method was used to monitor memantine hydrochloride in human urine in order to determine an appropriate sampling interval for future noninvasive therapeutic drug monitoring. The assay could also be applied to the determination of amantadine. The described assay showed that a postdosing time interval of 25-75 h seems adequate for sampling and monitoring memantine in urine.

Postmortem memantine concentrations.

Postmortem fluid and tissue concentrations of memantine (Namenda), a drug recently approved for the treatment of Alzheimer's Disease by the FDA, are reported in a suspicious death. In addition, memantine concentrations considered to be incidental findings in three other cases are included to aid in the interpretation in future toxicological investigations. Memantine was extracted from biological samples by a standard liquid-liquid basic drug method followed by analysis utilizing a gas chromatograph-mass spectrometer operated in SIM mode. Blood concentrations ranged from 0.03 to 1.8 mg/L, and the liver concentration was 6.1 mg/kg.

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

Influence of urine pH and urinary flow on the renal excretion of memantine.

AIMS: The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA-receptor antagonist memantine. METHODS: In a randomized, open, four-period cross-over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow). RESULTS: The renal clearance of memantine (CL(R)) in regimen A and B was 7-10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CL(R) between the two regimens with acidic urine pH (A: median: 210.2 ml min(-1) vs B: median: 218.7 ml min(-1)) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min(-1) vs D: median: 30.5 ml min(-1)). The amount of memantine excreted into the urine within one regimen (Ae0-24h) was 5.7-7.4 fold higher in regimens A and B than C and D (P< 0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D. CONCLUSIONS: The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.