Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects.

OBJECTIVES: Methantheline is a strong muscarinic receptor blocking drug used in the treatment of overactive bladder syndrome, hypersalivation and hyperhidrosis. To provide basic information on the pharmacokinetics, magnitude of pharmacodynamic (PD) effects and their correlations with plasma concentrations, we performed a clinical study in 12 healthy subjects receiving methantheline as immediate-release coated tablets (IR) or in watery solution (SOL) in comparison with atropine and placebo tablets. METHODS: The pharmacokinetics and influence of methantheline, atropine and placebo on salivation and accommodation and pupil function (pupillometry: diameter, response to light flash) were studied in a randomized, controlled study after the administration of 100 mg methantheline bromide as IR and in SOL (phase 1) and 1.0 mg atropine sulphate and placebo (phase 2). RESULTS: Methantheline reached maximum plasma concentrations of approximately 25 ng/ml after 2.5-3 h and was eliminated at an apparent half-life of approximately 2 h. There was no pharmacokinetic (PK) bioequivalence of methantheline IR and SOL. The ratio IR/SOL (90 % confidence interval) were 0.892 (0.532-1.493) for AUC(0-∞) and 0.905 (0.516-1.584) for maximum plasma concentration. The PD effects of both forms were nearly equivalent with a IR/SOL ratio of 1.015 (0.815-1.262) for salivation, which is the most susceptible characteristic. Methantheline reduced salivation at a potency (methantheline concentration at half maximum effects, EC50) of 5.5 ng/ml in accordance with it plasma concentration. The antimuscarinic effects observed after methantheline administration were stronger and persisted longer than those following the administration of atropine. CONCLUSIONS: Methantheline is slowly absorbed but rapidly eliminated in humans, and it exerts a strong effect on salivation which is closely associated with its plasma concentrations following a standard sigmoid PD model. Immediate-release tablets and a watery solution of methantheline are equivalent in terms of major PD effects (salivation, pupil function, heart rate) despite its high PK variability.

Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition.

OBJECTIVE: Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates. METHODS: Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration. RESULTS: Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration. CONCLUSIONS: Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.

Variability of intestinal expression of P-glycoprotein in healthy volunteers as described by absorption of talinolol from four bioequivalent tablets.

The beta(1)-selective blocker talinolol is incompletely absorbed in man from an "absorption window" in the upper small intestine which is under control of P-glycoprotein. The following single dose, four-period, changeover study with 7 days washout in 36 healthy subjects (21 females, age 20-33 years) was designed to confirm bioequivalence of four marketed tablet formulations of talinolol with identical in vitro liberation and to deduce from the intrasubject and intersubject variability of talinolol pharmacokinetics on the variability of intestinal P-gp function. All point estimates of the primary criteria AUC(0-infinity) and C(max) for the comparison of the galenic forms were within 0.9-1.10. The 90% confidence intervals were entirely within the standard ranges of bioequivalence (0.80-1.25 for AUC(0-infinity), 0.70-1.43 for C(max)). The intra- and intersubject coefficients of variation for AUC(0-infinity) were 14.0% and 20.4-29.5%, respectively. In conclusion, the four talinolol tablets are bioequivalent in extent and rate of absorption. The low intrasubject variability of the AUC(0-infinity) after weekly administration of the tablets refers to a small intrasubject variability of the "absorption window" and elimination of talinolol that most likely depends on the expression of P-gp in the small intestine.

Stereoselective disposition of talinolol in man.

The disposition of the beta-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22-26 years, body weight 67-84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(-) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(-) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(-) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(-) talinolol (p < 0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Cl(int) values of S(-) were higher than of R(+) talinolol; 0.1 microM ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man.

Adrenoceptor agonist poisoning after accidental oral ingestion of brimonidine eye drops.

OBJECTIVE: Brimonidine tartrate is a relatively selective alpha(2) adrenic agonist that lowers elevated intraocular pressure. A 2-yr-old boy presented with severe cardiorespiratory symptoms of systemic alpha(2) adrenergic intoxication after accidentally ingesting 2 mL of brimonidine ophthalmic solution (0.2%) orally. At 20 mins after ingestion, he became acutely pale and lethargic, with shallow infrequent respirations. The symptoms resolved completely within the next 10 hrs. METHODS: The pharmacokinetics of brimonidine in plasma and urine were analyzed using gas chromatography and mass spectrometry. RESULTS: Maximum plasma concentrations were 40 ng/mL 5 hrs after ingestion. The plasma elimination half-life value was 2.7 hrs. Elimination via urine was calculated as having a terminal half-life value of 3.2 hrs. CONCLUSIONS: This case illustrates the ability of brimonidine to gain rapid access to the central nervous system. This first passage is followed by a redistribution phase with rising plasma concentrations. Children who accidentally ingest brimonidine orally should be admitted to a pediatric intensive care unit.