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Grange et al., (2001). A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.

May 2013, model of the month by Stuart Moodie
Original models: BIOMD0000000320, BIOMD0000000321

Parkinsons's Disease is a neurodegenerative disease that affects an estimated 7 million people globally. Its most obvious symptoms are involuntary tremors, rigidity and slowness of movement. The disease is caused by the reduced activity of dopamine secreting cells, due to premature cell death, which leads to a deficiency of dopamine neurotransmission in the striatum [1]. The obvious treatment is to replace the depleted dopamine by administering dopamine to the patient. However, dopamine cannot cross the blood-brain barrier and is degraded when administered orally. A dopamine precursor L-dopa is used instead. This does cross the blood-brain barrier and is readily absorbed into the blood stream and has been the most widely used treatment for Parkinson's Disease for over 30 years.

L-dopa is decarboxylated into dopamine by the enzyme amino acid decarboxylase (AADC) and into 3-O-methyl-dopa (3-OMD) by catechol-O-methyltransferase (COMT), which effectively inactivates it (summarised in figure 1). Typically 69% of L-dopa is activated by AADC and 10% converted to 3-OMD [2]. Unfortunately, the production of dopamine from L-dopa outside the brain can cause side-effects such as nausea and heart palpitations. For this reason a peripheral AADC inhibitor, such as Benserazide (seryl-trihydroxybenzylhydrazine), is administered together with L-dopa to counteract this. Benserazide is metabolised to Ro 04-5127 (trihydroxybenzylhydrazine), mainly in the gut, and it was thought that the metabolised form inhibits AADC (see figure 1).

Figure 2

Figure 2 Schematic diagram of conceptual model to describe kinetics of L-dopa and 3-OMD (Q hepatic blood flow, L-dopa: CLAADC clearance via AADC, CLAADC0 clearance via AADC (no inhibition), CLCOMT clearance via COMT, CLdopa total clearance, CLH hepatic clearance, CLREST clearance via other elimination pathways, fAADC fraction metabolized by AADC, fCOMT fraction metabolized by COMT, fH hepatic fraction of total L-dopa clearance, Vdopa volume of distribution, F bioavailability (FG ? FH), FH hepatic availability, FG gastrointestinal availability, kai absorption rate constant; 3-OMD: CLOMD,i clearance, VOMD,i volume of distribution; Ro 04-5127: ki inhibition constant). Figure taken from [3].

The authors constructed a multi-compartment model that described the kinetics of L-dopa (figure 2) and Bensarazide (figure 3). The model was used to simulate two treatments: (1) 80mg/kg body weight L-dopa, (2) 80 mg/kg L-dopa and 20 mg/kg Bensarazide. To model the second treatment it was necessary to model the competitive inhibition by Ro 04-5127 and so the following term was used to describe L-dopa clearance mediated by AADC: CL_AADC = CL_AADC0/(1+ C1_M/ki); where CL_AADC0 was the clearance without inhibition, C1_M was the concentration of R0 04-5127 and ki was the inhibition constant. This form of the model is stored as BIOMD0000000320.

Rats were put into 3 treatments groups of 6 each. The first 2 groups were dosed as described in treatments 1 and 2 above and observations taken for 24 hours. The third group was treated with 20mg of Bensarazide and observations taken for 4 hours after dosing. To estimate the model parameters the data from the third group was used estimate the parameters for the Benserazide/Ro 04-5127 kinetics. These parameters were fixed then the L-dopa kinetics were estimated. In this case the L-dopa only treatment group was used to estimate key parameters first, which were then fixed when the model was used to estimate the L-dopa and Bensarazide co-administration.

The model was consistent with the non-compartmental analysis of the experimental data carried out in the paper and the parameters were in good agreement with values reported elsewhere. In particular the estimated bioavailability of L-dopa, obtained from the model, was 21% which is also in agreement with the work of Iwamoto et. al. [4]. This model was the first to investigate the kinetics of Benserazide using a mechanistic model in which Ro 04-7127 is the active inhibitor of AADC a mechanism consistent with Burkard et. al. [5]. The authors found that a model that included this mechanism obtained a better fit to the experimental data when compared to one without.

Figure 1

Figure 1 The reactions affecting L-dopa in this model are summarised here using an SBGN Process Description map. See the text for details.

Grange et. al. [3] describe a mechanistic model that describes the pharmacometrics of L-dopa administration in rats, with and without an AADC inhibitor. In the paper they describe essentially one model with two variants and these variants have been submitted to BioModels as BIOMD0000000320 and BIOMD0000000321. Their aim was to provide a model that could improve our understanding of the interaction between L-dopa and Benserazide in humans and examine the hypothesis that Ro 04-5127.

Figure 3

Figure 3 Schematic diagram of conceptual model to describe kinetics of benserazide and Ro 04-5127 (benserazide: CLB total clearance, CLdB intercompartmental clearance, FB bioavailability, fm fraction metabolized, kaB absorption rate constant, V1B volume of central compartment, V2B volume of peripheral compartment; Ro 04-5127: CLM total clearance, CLdM intercompartmental clearance, kaM absorption rate constant, keM elimination rate constant, V1M volume of central compartment, V2M volume of peripheral compartment). Figure taken from [3].

To conclude this is a very nice illustration how modelling can be used to examine the kinetics of drug metabolism, combination drug therapy and to explore the plausibility of mechanisms of drug metabolism.

Bibliographic references

  1. Wooten, GF. Pharmacokinetics of levodopa. In C. D. Marsden and S. Faka (eds.), Movement Disorders, Butterworths, 1984 pp. 231–240.
  2. Nutt, JG. & Fellman, JH. Pharmacokinetics of levodopa. Clin. Neuropharmacol. 1984;7:35-49.
  3. Grange et al. A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats. Pharmaceutical Research. 2001, 18(8):1174-1184.
  4. Iwamoto et al. Effect of age on gastrointestinal and hepatic first-pass effects of levodopa in rats. J. Pharm. Pharmacol. 1987, 36(6):421-425.
  5. Burkard et al. Inhibition of decarboxylase of aromatic amino acids by 2,3,4-trihydroxybenzylhydrazine and its seryl derivative. Arch. Biochem. Biophys. 1964, 107:187-196.