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In order to compare the fates of end-chain-radiolabelled and repeat-unit-radiolabelled poly(β-malic acid)s after intravenous injection in mice, repeat-unit 14 C-radiolabelling of this biodegradable water-soluble polycarboxylic acid polymer was achieved starting from 14 C-aspartic acid. The activity of the resulting radioactive poly(β-malic acid) (sodium salt) ( Mw ∼ 20,000 as determined by aqueous SEC) was 4.5 μCi·g -1 . Aliquots of a neutral 0.3 monoM (4.14% w/v) solution of poly(β-malic acid) (sodium salt) were given intravenously to mice through a lateral tail vein. Intravenous and intraperitoneal toxicity was checked in order to show whether injection of this polymer can affect significantly the normal behavior of experimental animals. Radioactivity was counted in liver, kidney, intestine, lung, brain, spleen, heart, muscle, urine and blood for various post-injection times up to 24 h. Data confirmed the occurrence of predominant and fast urinary excretion (70% after 1 h) already observed with the end-chain-radiolabelled homologue. Although the polymer is basically metabolizable, the fast elimination of radioactivity via urinary tract is most likely to be due to the excretion of polymeric molecules and not of metabolic by-products because end-chain-and repeat-unit-labellings led to similar excretion patterns.

To determine whether degradation could influence the in vivo elimination pattern of poly(β-malic acid) in mice, radioactive urinary excretion and 14CO2 expiration were studied after intravenous injection of 14C-radiolabeled poly(β-malic acid) and of its precursor, 14C-malate. The precursor administration led to rapid 14CO2 exhalation, and only negligible urinary elimination. The reverse was observed for the polymer. It was concluded that: (i) the in vivo degradation of poly(β-malic acid) chains, if any during the 24-h period of the study, did not release detectable malate molecules, (ii) the large urinary excretion of poly(β-malic acid) was due to the molar masses being less than the renal filtration threshold, (iii) the degradation of the poly(β-malic acid) chains in blood was slow enough to allow the fraction with higher molar masses to enter the interstitial space of the tissues, and possibly cells.

In a first attempt to determine the fate of poly(β-malic acid) after intravenous injection in mice, polymer end-chain 14C-radiolabelling was achieved using 14C-triethylamine as the initiator for the ring-opening polymer ization of benzyl malolactonate. The corresponding poly(β-malic acid) sodium salt ( Mw ∼ 30,000) exhibited an activity of 4.2 μCi :g-1. Aliquots of a neutral isoosmotic solution of the latter were given intravenously to mice through a lateral tail vein. Radioactivity was counted in the liver, kidney, intestine, lung, brain, spleen, heart, muscle, urine and blood for various post-injection times up to 24 hours. Fast urinary excretion (70% after 1 hour and 90% after 6 hours) was observed. For all the sites investigated, radioactivity decreased exponen tially except in the liver and kidneys where a small peak was detected after 2 hours. Further investigations with poly(β-malic acid) radiolabelled in repeat ing units will be necessary to overcome the shortcomings of the end-chain radiolabelling method applied to degradable polymers.

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Macromolecules (substitutive enzymes, polymeric prodrugs, immunotoxins, radiolabeled antibodies, or peptide hormones) are of interest in the treatment of several diseases. To reach the tissues, these macromolecular drugs have to cross the capillary wall, which represents an important transfer limitation. While pharmacokinetics usually studies the changes in drug concentration in different body compartments, analyzing the amount of drug gaining access to its target may be more relevant for assessing the efficiency of macromolecules than for low molecular mass drugs. To determine the influence of different parameters on the fraction of the injected dose gaining access to the pharmacologic target, we constructed pharmacokinetic models where two uptakes, both linear or nonlinear, work either in the same compartment (no transport limitation), or in compartments separated by a transport barrier. Numerical applications were carried out with parameters obtained either experimentally or from the literature. We conclude that it is of little use to increase the affinity (K(uptake)) of a macromolecular drug for its target when a transport limitation and an undesired elimination from the plasma space are both present. Likewise, an increase of the uptake (rate of uptake or maximal velocity) by the target is not very productive because permeability of the capillary wall is the factor limiting access of macromolecules to tissues. Maximal efficiency of therapeutic macromolecules could be achieved by increasing, where feasible, the transport across the barrier between the plasma and the target, and by preventing the undesired eliminations as much as possible.

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