P. J. Pentikäinen

Pharmacokinetics of metformin after intravenous and oral administration to man.

SummaryThe kinetics of14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 (

Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone.

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Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver.

±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of “flip-flop” type for oral metformin.

Pharmacokinetics of flecainide in patients with cirrhosis of the liver

To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2α, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h−1), and longer elimination half‐life (7.36 vs 3.80 h). The bioavailability of oral midazolam was significantly (P < 0.05) higher in patients than controls (76% vs. 38%). The antipyrine‐half‐life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P < 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half‐lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.

Pharmacokinetics of intravenously administered bumetanide in man

The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers.Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h.Entacapone showed linear pharmacokinetics over the dose range studied: Cmax and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a tmax ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t1/2α of 0.27–0.37 h and t1/2β of 1.59–3.44 h.Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen.The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.

Bioavailability of Four Brands of Phenytoin Tablets

Twelve healthy male volunteers received single market‐image 40‐mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (α β‐hydroxyacid) at 1 week intervals in a three‐way crossover study to quantify HMG‐CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG‐CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG‐CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2–3 fold greater area under the concentration‐time curve) suggest a greater potential availability of pravastatin‐related inhibitory activity to peripheral tissues.

Pharmacokinetics of oral mexiletine in patients with acute myocardial infarction

SummaryThe pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or14C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.

Laboratory tests as predictors of the antihypertensive effects of amlodipine, bisoprolol, hydrochlorothiazide and losartan in men: results from the randomized, double-blind, crossover Genres Study

The pharmacokinetics of flecainide were studied in six patients with cirrhosis of the liver and in six healthy subjects after a single 2 mg/kg intravenous dose. Hepatic biotransformation capability before flecainide dosing was assessed by antipyrine challenge. The mean plasma antipyrine t½ for patients (42.2 hours) was longer (p < 0.01) than that for subjects (11.7 hours). For control subjects, the plasma t½ of flecainide (9.5 hours) was shorter (p < 0.01), plasma clearance (9.1 ml/min/kg) was faster (p < 0.01), and volume of distribution (7.5 L/kg) was smaller (p < 0.05) compared with corresponding values in patients. Renal clearance did not differ (p > 0.05) between the two groups. The mean ratio of renal clearance to plasma clearance for subjects (0.4) was smaller (p < 0.05) than that for patients. The slower rate of flecainide elimination from plasma in patients is likely due to reduced hepatic biotransformation. In patients with cirrhosis, plasma levels of flecainide may accumulate to unacceptably high levels with usual dosage regimens.