Pharmacokinetics of propranolol and atenolol in patients after partial gastric resection: a comparative study.

OBJECTIVE: Partial gastric resection alters the anatomy and secretory activity of the gastrointestinal tract. It might be expected that the consequences of such changes should affect the pharmacokinetics, especially concerning the absorption of orally administered drugs. Propranolol and atenolol, as representatives of lipophilic and hydrophilic beta-adrenoreceptor antagonists, have been studied in order to define their pharmacokinetic characteristics in patients after partial gastrectomy. METHODS: The study was carried out in 29 patients after gastric resection with Billroth I (B1) anastomosis and in 18 healthy volunteers as controls. Pharmacokinetics of propranolol and atenolol was investigated after a single oral dose of 80 mg and 100 mg, respectively, following a cross-over schedule. Blood samples were collected ten times during the 24 h after the drug administration. Pharmacokinetic parameters of propranolol and atenolol were calculated using a one-compartment open model with first-order absorption. RESULTS: The average blood plasma concentrations of propranolol in gastrectomised patients were lower than those in controls, reaching significance between 1.5 h and 6.0 h of the observation period. Pharmacokinetic parameters of propranolol were different in subjects submitted to surgery compared with healthy persons. We observed a significant decrease in the area under the concentration-time curve (32%) and the peak plasma concentration (20%), and an increase in half-life (25%). Mean plasma concentrations and pharmacokinetic parameters of atenolol in patients following partial gastric resection were not significantly different from those in the controls. No relationship between time interval following partial gastrectomy and pharmacokinetic parameters of the investigated drugs was noted. CONCLUSION: Partial gastrectomy with B1 anastomosis affects the pharmacokinetics of propranolol (lipophilic drug) but not atenolol (hydrophilic drug).

[Effect of hydroxylation polymorphism on the concentration of propranolol in the blood of humans with hyperlipidemia]. / Wplyw polimorfizmu hydroksylacji na stezenie propanololu we krwi u ludzi z hiperlipidemia.

An influence of hydroxylation phenotype on the concentration of propranolol [corrected] was examined in 52 subjects with hyperlipidemia divided into 4 groups: 1--control, normolipemic, 2--hypercholesterolemic, 3--hypertriglyceridemic, and 4--mixed-form hyperlipidemic. Each study group included extensive metabolizers and one subject characterized by a poor hydroxylation phenotype. Propranolol was given intragastrically at a single dose of 80 mg [corrected]. Blood was sampled within 24 hours following the drug administration. HPLC method was used for determining blood serum concentrations of propranolol. In each study group mean blood serum concentrations of propranolol in poor metabolizers were at maximum in subject with hypertriglyceridemia, at minimum in the normolipemic one, and intermediate in hypercholesterolemic (upper) and mixed-form hyperlipidemic ones. Lipid metabolic disturbances also affected blood serum concentrations. They were the highest in hypertriglyceridemic patients, whereas in hypercholesterolemic were, in early stage of observation, even lower then in normolipemic subjects. Blood serum concentrations of propranolol [corrected] attained minimal values in patients with mixed form of hyperlipidemia. In the light of the present study we can state that hyperlipidemia modifies the blood serum concentrations of propranolol [corrected]. Although, the type of hyperlipidemia and lipophilic propranolol are not the only determinants affecting blood serum concentrations of propranolol, but also a genetic factor, i.e. hydroxylation phenotype may play an important role.

[The effect of hypolipemic treatment on the pharmacokinetics of propranolol]. / Wplyw leczenia hipolipemicznego na farmakokinetyke propranololu.

The influence of elevated concentration of lipids in blood on the concentration of drugs in organism was observed in 1976. The following experiments have revealed that pharmacokinetics of lipophilic drugs in hyperlipidemia is altered. The purpose of this paper was to evaluate the effect of hypolipemic treatment on the propranolol pharmacokinetics, to take into account phenotype of hydroxylation and type of primary hyperlipidemia. The study was carried out on 37 patients (34 patients EM and 3 patients PM) with hypercholesterolemia, hypertriglyceridemia and mixed form of hyperlipidemia. Duration of hypolipemic therapy was 30 days. Pharmacokinetic studies were carried out twice i.e. at the onset of the study and following a 30-day period of hypolipemic treatment. Propranolol was given orally as a single dose 80 mg. Blood serum was sampled during administration. HPLC method was used to determine blood serum concentration of propranolol. The one-compartment model was applied for calculation of pharmacokinetic parameters. The obtained results have disclosed that hypolipemic therapy altered pharmacokinetic parameters of propranolol. Intensity and course of these changes depend on the type of hyperlipidemia. The most pronounced changes were observed in patients EM with hypertriglyceridemia. Lowering of propranolol concentration in blood, elevated penetration into tissues and accelerated elimination were revealed (Fig. 3, 4). Similar changes, but lesser intensity were observed in patients with mixed form of hyperlipidemia (Fig 5, 6). Alteration of pharmacokinetic parameters of propranolol in hypercholesterolemic patients were slight and contrasting the patients with hypertriglyceridemia and mixed form of hyperlipidemia. The lowering of cholesterol concentration in blood has slight influence on normalization of propranolol kinetics (Fig 1, 2). In patients with phenotype PM pharmacokinetic parameters of propranolol were changed, under used treatment too. Due to the limited number of patients, conclusions should be carefully drawn. The actual results have disclosed a decrease in lipids concentration, mainly triglycerides, which causes changes in pharmacokinetics of propranolol in patients with phenotype PM as well.

Debrisoquine hydroxylation in a Polish population.

The genetic polymorphism of drug oxidation mediated by cytochrome P450IID6 (CYP2D6) was determined in 154 Polish volunteers using debrisoquine as the test substance. The results showed a bimodal distribution of the debrisoquine metabolic ratio (MR). Nine persons (5.8%) with MR > 12.6 were classified as poor metabolisers (gene frequency 0.242), which is in substantial agreement with the data reported for other Caucasian populations.