venlafaxine (Effexor)
The effect of renal disease on the disposition of venlafaxine.

Troy SM, Schultz RW, Parker VD, Chiang ST, Blum RA.

Department of Medicine, Millard Fillmore Hospital, Buffalo, NY 14209-1194.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8033490&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in laboratory animals.

Howell SR, Hicks DR, Scatina JA, Sisenwine SF.

Drug Metabolism Division, Wyeth-Ayerst Research, Princeton, NJ 08543-8000.

1. The pharmacokinetics of venlafaxine have been evaluated in mouse, rat, dog and rhesus monkey after i.v. and/or i.g. doses of venlafaxine from 2 to 120 mg/kg either as single or repeated doses. 2. In rat, dog and monkey, venlafaxine is a high clearance compound with a large volume of distribution after i.v. administration. 3. Absolute bioavailability was low in rat and rhesus monkey (12.6 and 6.5%, respectively) and moderate in dog (59.8%). Other species differences were seen, including an elimination half-life of venlafaxine that was longer in dog and rhesus monkey (2-4 h) than in rodent (around 1 h). 4. In mouse, rat and dog, exposure to venlafaxine increased more than proportionally with dose, suggesting saturation of elimination. Exposure of venlafaxine decreased with repeated dosing in mouse and rat, but was unchanged in dog. 5. Exposure of animals to the bioactive metabolite, O-desmethylvenlafaxine (ODV), was less than that of venlafaxine itself. ODV was not detected in dog and not measurable in rhesus monkey receiving venlafaxine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8059535&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
A high-performance liquid chromatographic method for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in biological fluids.

Hicks DR, Wolaniuk D, Russell A, Cavanaugh N, Kraml M.

Drug Metabolism Division, Wyeth-Ayerst Research, Princeton, New Jersey 08540.

A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method for simultaneous determination of venlafaxine (V) and O-desmethylvenlafaxine (ODV) in plasma and urine has been developed. V and ODV are extracted from plasma using a liquid-liquid extraction procedure, chromatographed on a Supelcosil LC-8DB column, and quantitated by UV detection at 229 nm. Linearity was established over the range 10-500 ng/ml for V and 7.2-720 ng/ml for ODV using 1.0 ml of human, rat, dog, and mouse plasma. For urine, for both analytes, an analytical range 0.1-10.0 micrograms/ml was established. Accuracy of > +/- 10% about the theoretical mean was achieved for all matrices, with intra- and interday coefficients of variation for precision of < 10%. Endogenous components in plasma and/or urine or known metabolites of V do not interfere in the determination of the analytes. For both V and ODV a quantitation limit of 10 ng/ml for plasma was adequate for their estimation over a period of three half-lives, following administration of a pharmacologic dose in man, and the limit of 0.1 microgram/ml, for urine, can monitor excretion of as little as 0.5% of the dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8160247&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Venlafaxine exhibits pre-clinical antidepressant activity in the resident-intruder social interaction paradigm.

Mitchell PJ, Fletcher A.

Neuropharmacology Group, Wyeth Research Ltd, Maidenhead, Berkshire, U.K.

Venlafaxine, a novel 2-phenyl-2-(1-hydroxycycloalkyl) ethylamine, is a potent inhibitor of 5-hydroxytryptamine and noradrenaline reuptake and exhibits a profile of activity in pre-clinical in vitro biochemical studies predictive of antidepressant activity. The studies described here examined the effects of acute and chronic treatment with venlafaxine on the behaviour of resident rats confronted with an unfamiliar, non-treated, intruder conspecific. Ethological analysis of the social encounters revealed that acute, subcutaneous, treatment with venlafaxine, 20-180 mumol kg-1, induced a selective, dose-related, reduction in aggressive behaviour (ID50 = 24.87 mumol kg-1) concomitant with increased flight behaviour. In contrast, chronic treatment with venlafaxine, 20 mumol kg-1 day-1, via subcutaneously-implanted osmotic mini-pumps, induced a marked elevation in aggressive behaviour concomitant with reduced flight behaviour. These diametrically opposite effects of acute and chronic venlafaxine treatment on the agonistic behaviour of resident rats are consistent with the behavioural effects of similar treatment regimes previously identified for a range of antidepressant drugs that differ widely in their acute pharmacology. These data strongly support the potential antidepressant activity of venlafaxine and are consistent with the results of recent clinical trials which demonstrate that venlafaxine exhibits significant antidepressant activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8295710&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Metabolic disposition of 14C-venlafaxine in mouse, rat, dog, rhesus monkey and man.

Howell SR, Husbands GE, Scatina JA, Sisenwine SF.

Drug Metabolism Division, Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543-8000.

1. The metabolic disposition of venlafaxine has been studied in mouse, rat, dog, rhesus monkey and man after oral doses (22, 22, 2, and 10 mg/kg, and 50 mg, respectively) of 14C-venlafaxine as the hydrochloride. 2. In all species, over 85% of the administered radioactivity was recovered in the urine within 72 h, indicating extensive absorption from the GI tract and renal excretion. 3. Venlafaxine was extensively metabolized, with only 13.0, 1.8, 7.9, 0.3 and 4.7% dose appearing as parent compound in urine of mouse, rat, dog, monkey and man, respectively. The metabolite profile varied significantly among species, but primary metabolic reactions were demethylations and the conjugation of phase I metabolites. Hydroxylation of the cyclohexyl ring also occurred in mouse, rat and monkey, and a cyclic product was formed in rat and monkey. Glucuronidation was the primary conjugation reaction, although sulphate conjugates were also detected in mouse urine. 4. While no metabolite constituted more than 20% dose in any species except man, the major urinary metabolites were: mouse, N,O-didesmethyl-venlafaxine glucuronide; rat, cis-1,4-dihydroxy-venlafaxine; dog, O-desmethyl-venlafaxine glucuronide; monkey, N,N,O-tridesmethyl-venlafaxine; and man, O-desmethyl-venlafaxine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8337893&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR