摘要:

Buprenorphine is a semi-synthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy,Papaver somniferum. The pharmacology of buprenorphine is unique in that it is a partial agonist at the opioid μ receptor. Buprenorphine undergoes extensive first-pass metabolism and therefore has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for the treatment of opioid dependence. The mean time to maximum plasma concentration following sublingual administration is variable, ranging from 40 minutes to 3.5 hours. Buprenorphine has a large volume of distribution and is highly protein bound (96%). It is extensively metabolised byN-dealkylation to norbuprenorphine primarily through cytochrome P450 (CYP) 3A4. The terminal elimination half-life of buprenorphine is long and there is considerable variation in reported values (mean values ranging from 3 to 44 hours). Most of a dose of buprenorphine is eliminated in the faeces, with approximately 10–30% excreted in urine. Naloxone has been added to a sublingual formulation of buprenorphine to reduce the abuse liability of the product. The presence of naloxone does not appear to influence the pharmacokinetics of buprenorphine. Buprenorphine crosses the placenta during pregnancy and also crosses into breast milk. Buprenorphine dosage does not need to be significantly adjusted in patients with renal impairment; however, since CYP3A activity may be decreased in patients with severe chronic liver disease, it is possible that the metabolism of buprenorphine will be altered in these patients. Although there is limited evidence in the literature to date, drugs that are known to inhibit or induce CYP3A4 have the potential to diminish or enhance buprenorphineN-dealkylation. It appears that the interaction between buprenorphine and benzodiazepines is more likely to be a pharmacodynamic (additive or synergistic) than a pharmacokinetic interaction. The relationship between buprenorphine plasma concentration and response in the treatment of opioid dependence has not been well studied.The pharmacokinetic and pharmacodynamic properties of buprenorphine allow it to be a feasible option for substitution therapy in the treatment of opioid dependence.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Hydroxyethyl starch has recently become the subject of renewed interest because of the introduction of a new specification, hydroxyethyl starch 130/0.4, as well as the clinical availability of a solution using a previous hydroxyethyl starch type (hydroxyethyl starch 670/0.75) with a carrier other than 0.9% saline.Various types of hydroxyethyl starch show different pharmacokinetic behaviour. Since hydroxyethyl starch is a polydisperse solution acting as a colloid, pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; therefore, solutions with a lowerin vivomolecular weight contain more molecules at similar plasma concentrations. On the other hand, high plasma concentrations as well as highin vivomolecular weight can affect blood coagulation, especially factor VIII and von Willebrand factor.Hydroxyethyl starch types with a molar substitution >0.4 accumulate in plasma after repetitive administration, most pronounced with hetastarch (hydroxyethyl starch 670/0.75). Correspondingly, tissue storage as measured by14C tracer studies  in  animals  showed  significantly  higher  values  for  hydroxyethyl starch 200/0.5 compared with hydroxyethyl starch 130/0.4 (about 4-fold at the latest timepoint  after  the  last  administration),  and  considerably  higher  values  for hetastarch compared with both hydroxyethyl starch 130/0.4 and 200/0.5.Hydroxyethyl starch 130/0.4 does not accumulate in plasma after single- and multiple-dose administration in contrast to all other available hydroxyethyl starch specifications. Plasma clearance of hydroxyethyl starch 130/0.4 is at least 20-fold higher than that for hetastarch, and considerably higher than for pentastarch. In patients with renal insufficiency, pharmacokinetic data are only available for hydroxyethyl starch 130/0.4. Cumulative urinary excretion, even in the presence of severe non-anuric renal failure, is higher for hydroxyethyl starch 130/0.4 than values published for older hydroxyethyl starch specifications. Hydroxyethyl starch 130/0.4 may be given to patients with severe renal impairment as long as urine flow is preserved.The pharmacodynamics with respect to the volume effect does not directly mirror pharmacokinetics in the case of hydroxyethyl starch solutions. Equivalent volume efficacy has been proven for hydroxyethyl starch 130/0.4 compared with 200/0.5. Prolonged persistence of hydroxyethyl starch in plasma and tissues can be avoided by using rapidly metabolisable hydroxyethyl starch types with molar substitution <0.5. Influence on coagulation is minimal with hydroxyethyl starch 130/0.4, and no adverse effects on kidney function have been observed even with large repetitive doses when used according to the product information.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Trospium chloride, a quaternary amine with anticholinergic properties, is used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. The pharmacokinetics of trospium chloride have been investigated in healthy volunteers, in patients with renal and hepatic impairment, and in those with symptoms of overactive bladder, after oral, intravenous and intravesical administration.After oral administration, absorption of the hydrophilic trospium chloride is slow  and  incomplete.  Peak  plasma  concentrations  (Cmax)  of  approximately 4 ng/mL are reached 4–5 hours after administration of a 20mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmaxafter a single dose within the clinically relevant dose range (20–60mg). The mean volume of distribution is approximately 350–800L. The drug is minimally (mean approximately 10%) metabolised to spiroalcohol by hydrolysis, is 50% plasma protein bound and does not cross the blood-brain barrier. Urinary excretion of the parent compound plays a major role in the disposition of the drug, with a mean renal clearance of 29 L/h (accounting for approximately 70% of total clearance) and a mean elimination half-life ranging from 10 to 20 hours. Elimination of the drug is slowed in patients with renal insufficiency, and population pharmacokinetic modelling has demonstrated that drug clearance is correlated with serum creatinine concentration. Thus, dose reduction is needed in patients with severe renal impairment (i.e. creatinine clearance <30 mL/min).To date, no clinically relevant pharmacokinetic drug-drug interactions have been identified; the drug does not bind to any of the drug metabolising cytochrome P450 enzymes.The pharmacokinetics of the drug are compatible with twice-daily administration. A once-daily schedule may also be appropriate, but this regimen needs formal clinical evaluation.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveMetformin is an effective treatment for type 2 diabetes mellitus. The pharmacokinetic characteristics of the conventional immediate-release (IR) formulation of metformin (Glucophage®), however, necessitate two- or three-times-daily dosing. Development of a novel extended-release (XR) formulation of metformin (Glucophage®XR) using GelShield Diffusion System technology provides a once-daily dosing option. The objective of this study was to assess the steady-state pharmacokinetics of metformin XR tablets.Study designThis was an open-label, multiple-dose, five-regimen, two-sequence clinical study lasting 5 weeks.MethodsSubjects were 16 healthy volunteers aged 18–40 years. Three 1-week regimens of metformin XR (500, 1000 and 1500mg once daily) were administered sequentially. Subjects were alternately given either metformin XR 2000mg once daily or metformin IR 1000mg twice daily during weeks 4 and 5. The pharmacokinetic properties of metformin XR were assessed on two separate days at steady state and compared with those of metformin IR.ResultsAbsorption of metformin XR was slower than that of metformin IR (time to maximum plasma concentration = 7 versus 3 hours). Maximum plasma concentrations (Cmax) following the administration of metformin XR 2000mg once daily was 36% higher than that following the evening dose of metformin IR 1000mg twice daily. The extent of absorption, determined by area under the plasma concentration-time curve (AUC), was equivalent for both formulations. The mean accumulation ratio of metformin XR was 1.0, indicating no accumulation with multiple-dose administration. Intrasubject variabilities in Cmaxand AUC of metformin were comparable between metformin XR and metformin IR. This novel formulation of metformin XR was well tolerated at single doses up to 2000mg once daily for 7 days, and adverse events were similar to those reported with metformin IR.ConclusionThe pharmacokinetic parameters of metformin XR tablet using GelShield Diffusion System technology were similar to those of metformin IR. Metformin XR was well tolerated at single doses up to 2000mg once daily.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveLevo-α-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequentialN-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomalN-demethylationin vitrois catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humansin vivois unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect.MethodsHealthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model.ResultsCompared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC∞199 ± 91 [control] versus 11.3 ± 4.0 [rifampicin] and 731 ± 229 ng · h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC96) [norLAAM + dinorLAAM] (859 ± 241 versus 107 ± 48 and 1185 ± 179 ng · h/mL; p < 0.05) and clinical effects (mean miosis AUC96128 ± 40 versus 22.5 ± 14.9 and 178 ± 81 mm · h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations.ConclusionCYP3A mediates human LAAMN-demethylation and bioactivation to norLAAM and dinorLAAMin vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validatein vitrodrug metabolism studies.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveTo determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers.MethodsCocaine 20 or 40mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days.ResultsTwelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40mg cocaine infusions, but the reduction was only statistically significant after the 40mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine.ConclusionThis study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS