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

The effect of obesity induced by a high-fat diet on the pharmacokinetics (PK) of nelfinavir (NFV) was investigated, focusing on the change of distribution and elimination caused by dyslipidemia and hepatic steatosis.The plasma unbound fraction (f(u)) of NFV in obese rats (0.61+/-0.03%) was significantly lower than in the control (1.10+/-0.09%), caused by increasing the plasma triglyceride-rich lipoprotein level. After intravenous (i.v.) administration of NFV, the marked decrease of the distribution volume and slower total clearance (39.5% and 69.1% of the control, respectively) caused by the lower f(u) were the main reasons for the significantly higher area under the blood concentration versus time curve (AUC) in obese rats (145.3% of the control). The absorption of NFV after intraduodenal (i.d.) administration in obese rats was significantly greater than in the control (AUC; 170.4% of the control). The increased bile in obese rats was the main reason for the increasing absorption of NFV, and the lower expression of intestinal P-glycoprotein was also considered. On the other hand, although higher AUCs in obese rats were shown, unbound AUCs in the obese rats were slightly lower than in the control, namely, the plasma NFV concentration in obese rats to obtain the same pharmacological effect was higher than in the control, suggesting the difficulty of drug monitoring. These results suggest that it is necessary to pay further attention to therapeutic drug monitoring of NFV in patients manifesting metabolic syndrome, such as dyslipidemia and visceral fat accumulation, including hepatic steatosis.
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PMID:Effects of obesity induced by high-fat diet on the pharmacokinetics of nelfinavir, a HIV protease inhibitor, in laboratory rats. 1986 65

Patients with rare homozygous familial hypercholesterolaemia are at risk of dying at a very young age. When liver transplantation is not feasible, treatment is based on regular LDL apheresis sessions, a burdensome and inconvenient procedure, and on high-dose statins in combination with ezetimibe. Lomitapide acts by inhibiting the synthesis of LDL constituents. It has been granted EU marketing authorisation as adjunctive therapy for homozygous familial hypercholesterolaemia. Clinical evaluation of lomitapide is based on a non-comparative trial in 29 adults. When added to standard therapy, lomitapide led to about a 40% reduction in absolute LDL cholesterol levels. Longer follow-up is needed to determine whether this is sufficient to prevent cardiovascular complications. Seven of the 13 patients under-going LDL apheresis were able to increase the interval between sessions or stop them altogether. Nearly all patients treated with lomitapide experienced gastrointestinal adverse effects, including diarrhoea, nausea, vomiting and dyspepsia. Lomitapide was associated with hepatic abnormalities in about one-third of patients in the short-term. It remains to be seen whether the hepatic steatosis observed in some patients progresses to fibrosis or cirrhosis with long-term use. Lomitapide is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 and also inhibits P-glycoprotein, hence a risk of multiple pharmacokinetic interactions. In particular, lomitapide increases the plasma concentrations of statins, and their toxicity. Lomitapide was teratogenic in experimental animals. In practice, lomitapide should be strictly reserved for patients with homozygous familial hypercholesterolaemia. Clinical evaluation must continue in these rare patients at high risk of early death.
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PMID:Iomitapide (Lojuxta). Use only in homozygous familial hypercholesterolaemia, with caution. 2624 Aug 81