Pharmacokinetic considerations in development of a bioartificial liver.

Abstract

We consider the pharmacokinetics of bioartificial livers (BALs) prepared using a hollow fibre module with respect to two key functions, detoxification and plasma protein supply, and present the results in a simple form. We then discuss the advantages and disadvantages of BAL therapy in comparison with the non-biological therapies of haemodialysis and plasma exchange. Nitrogenous and other potentially toxic compounds, such as ammonia, mercaptans, short-chain fatty acids and gamma-aminobutyric acid, are produced in the bowels and accumulate in the systemic blood because of impaired elimination by the ailing liver. Adrenal and gonadal steroids, including corticosteroids, estrogens, progestins and androgens, are biosynthesised, and high concentrations of these hormones become harmful. All these endogenously produced toxins require effective metabolism. In haemodialysis, toxins that permeate through the hollow fibre membrane are rapidly removed by the dialysate flow, and their concentrations decrease to almost zero. In a BAL bioreactor, the toxins are slowly metabolised by hepatocytes in the hollow fibres, and decreased to concentrations that are inversely proportional to the number of hepatocytes in the BAL, even after a long-term assist. It is difficult to rationalise the clinical usage of BAL systems containing small amounts of hepatocytes (70-100g) to remove the toxins. Concentrations of plasma proteins in a patient after long-term BAL treatment are proportional to the number of hepatocytes in the device. BAL reactors prepared using porcine hepatocytes supply porcine proteins, not human proteins, to the recipient. Plasma exchange increases protein concentrations much more effectively than BAL as long as a sufficient amount of plasma is available. The blood inflow rate to the liver is about 1500 mL/min in a normal adult. On the other hand, blood draw rates to a BAL system are restricted to the range of 100-300 mL/min. Toxins that are rapidly cleared by the liver (for example, the ammonia clearance of the normal human liver is several hundred mL/min) cannot be effectively eliminated from the systemic blood by BAL systems currently under clinical evaluation. Hepatocytes are the only elements in a BAL reactor that can metabolise toxins and synthesise proteins, and thus BAL performance increases with the increasing number of hepatocytes in the bioreactor. The human liver weighs about 1500 g and contains about 80% hepatocytes, i.e. about 1200 g of hepatocytes. The blood flow through the liver is about 1500 mL/min in a normal adult. To effectively replace liver functions would require a BAL reactor containing the functional equivalent of several hundreds of grams of human hepatocytes with an extracorporeal perfusion rate of more than 1000 mL/min. At this point, only orthotopic liver transplantation can meet these criteria.