###  Absorption

Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. COREG CR extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages [see Dosage and Administration (2)], the exposure (AUC, Cmax, trough concentration) of carvedilol as COREG CR extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from COREG CR is slower and more prolonged compared with the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of COREG CR 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for COREG CR and immediate-release carvedilol.

####  Effect of Food

Administration of COREG CR with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with COREG CR administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when COREG CR was administered in the fasted state compared with administration after a standard meal. COREG CR should be taken with food.

In a trial with adult subjects, sprinkling the contents of the COREG CR capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared with administration of the intact capsule following a standard meal but did result in a decrease in Cmax (18%).

###  Distribution

Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.

###  Metabolism and Excretion

Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β‑receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β‑blockade.

Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.

Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of COREG CR in healthy subjects. Apparent clearance is 90 L per h and 213 L per h for R(+)- and S(-)-carvedilol, respectively.

The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.

Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).