Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The succinate salt of solifenacin, a tertiary amine with anticholinergic properties, is used for symptomatic treatment of overactive bladder. Solifenacin peak plasma concentrations of 24.0 and 40.6 ng/mL are reached 3-8 hours after long-term oral administration of a 5 or 10 mg solifenacin dose, respectively. Studies in healthy adults have shown that the drug has high absolute bioavailability of about 90%, which does not decrease with concomitant food intake. Solifenacin has an apparent volume of distribution of 600 L, is 93-96% plasma protein bound, and probably crosses the blood-brain barrier. Solifenacin is eliminated mainly through hepatic metabolism via cytochrome P450 (CYP) 3A4, with about only 7% (3-13%) of the dose being excreted unchanged in the urine. Solifenacin metabolites are unlikely to contribute to clinical solifenacin effects. In healthy adults, total clearance of solifenacin amounts to 7-14 L/h. The terminal elimination half-life ranges from 33 to 85 hours, permitting once-daily administration. Urinary excretion plays a minor role in the elimination of solifenacin, resulting in renal clearance of 0.67-1.51 L/h. Solifenacin does not influence the activity of CYP1A1/2, 2C9, 2D6 and 3A4, and shows a weak inhibitory potential for CYP2C19 and P-glycoprotein in vitro; however, clinical drug-drug interactions with CYP2C19 and P-glycoprotein substrates are very unlikely. Exposure to solifenacin is increased about 1.2-fold in elderly subjects and about 2-fold in subjects with moderate hepatic and severe renal impairment, as well as by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day. The full therapeutic effects of solifenacin occur after 2-4 weeks of treatment and are maintained upon long-term therapy. Although solifenacin pharmacokinetics display linearity at doses of 5-40 mg, no obvious dose dependency was observed in efficacy and tolerability studies. The efficacy of solifenacin (5 or 10 mg/day) is at least equal to that of extended-release (ER) tolterodine (4 mg/day) in reducing the mean number of micturitions per 24 hours and urgency episodes, and in increasing the volume voided per micturition. Solifenacin (5 mg/day) appears to be superior to ER tolterodine (4 mg/day) in reducing incontinence episodes (mean -1.30 vs -0.90, p = 0.018) and is superior to propiverine (20 mg/day) at the dose of 10 mg/day in reducing urgency (-2.30 vs -2.78, p = 0.012) and nocturia episodes. Based on withdrawal rates due to adverse effects during the 52-week treatment period, solifenacin appears to have better tolerability than immediate-release (IR) oxybutynin 10-15 mg/day and IR tolterodine 4 mg/day. With regard to the pharmacokinetics of solifenacin, and for safety reasons, doses exceeding 5 mg/day are not recommended for patients with moderate hepatic impairment (Child-Pugh score 7-9), patients with severe renal impairment (creatinine clearance <30 mL/min) and subjects undergoing concomitant therapy with CYP3A4 inhibitors.
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PMID:Clinical pharmacokinetics and pharmacodynamics of solifenacin. 1956 12

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, kidney pain, hypertension, and progressive loss of renal function. It is a leading cause of end-stage renal disease and the most common inherited kidney disease in the United States. Despite its prevalence, disease-modifying treatment options do not currently exist. Tolvaptan is an orally active, selective arginine vasopressin V2 receptor antagonist already in use for hyponatremia. Tolvaptan exhibits dose-proportional pharmacokinetics with a half-life of ~12 hours. Metabolism occurs through the cytochrome P450 3A4 isoenzyme, and tolvaptan is a substrate for P-glycoprotein, resulting in numerous drug interactions. Recent research has highlighted the beneficial effect of tolvaptan on delaying the progression of ADPKD, which is the focus of this review. Pharmacologic, preclinical, and phase II and III clinical trial studies have demonstrated that tolvaptan is an effective treatment option that targets underlying pathogenic mechanisms of ADPKD. Tolvaptan delays the increase in total kidney volume (surrogate marker for disease progression), slows the decline in renal function, and reduces kidney pain. However, tolvaptan has significant adverse effects including aquaretic effects (polyuria, nocturia, polydipsia) and elevation of aminotransferase enzyme concentrations with the potential for acute liver failure. Appropriate patient selection is critical to optimize long-term benefits while minimizing adverse effects and hepatotoxic risk factors. Overall, tolvaptan is the first pharmacotherapeutic intervention to demonstrate significant benefit in the treatment of ADPKD, but practitioners and regulatory agencies must carefully weigh the risks versus benefits. Additional research should focus on incidence and risk factors of liver injury, cost-effectiveness, clinical management of drug-drug interactions, and long-term disease outcomes.
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PMID:Review of tolvaptan for autosomal dominant polycystic kidney disease. 2470 79