Bioavailability and Pharmacokinetics of Oral Dopamine in Dogs

Murata, Kzuo; Noda, Kohei; Kohno, Keiichi; Samejima, Masayoshi

doi:10.1002/jps.2600770703

Cited by 12 publications

(6 citation statements)

References 4 publications

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“…This could be due to the metabolism of the drug during the absorption process. For example, in dogs, the first-pass metabolism of dopamine predominantly occurs in the small intestine, with an estimated bioavailability of only 3% and a half-life of 10.8 min ( 58 ). In contrast to dopamine, pramipexole and ropinirole, both of which showed a significant effect on the small intestinal motility ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This increased alteration in the proximal small intestinal microbiota composition upon exposure to PD medication implies that the medication has a stronger effect on the proximal small intestinal motility. This effect could be due to the rapid absorption of the drugs in the proximal small intestine ( 58 , 60 , 61 ), resulting in the highest local drug concentration in the proximal small intestine. Plausibly, these drugs could also elicit a direct effect on the microbiota, which warrants further elucidation.…”

Section: Discussionmentioning

confidence: 99%

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Parkinson’s Disease Medication Alters Small Intestinal Motility and Microbiota Composition in Healthy Rats

et al. 2022

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is known to be associated with altered gastrointestinal function and microbiota composition. We previously showed that the gut bacteria harboring tyrosine decarboxylase enzymes interfere with levodopa, the main treatment for PD (S. P. van Kessel, A. K. Frye, A. O. El-Gendy, M. Castejon, A. Keshavarzian, G. van Dijk, and S. El Aidy, Nat Commun 10:310, 2019).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Parkinson’s Disease Medication Alters Small Intestinal Motility and Microbiota Composition in Healthy Rats

et al. 2022

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“…For example, the first-pass metabolism of dopamine is predominant in the intestine of dogs and its oral bioavailability was only approximately 3% with a half-life of 10•8 minutes. 70 In contrast to dopamine, pramipexole and ropinirole, both of which showed a significant effect on small intestinal motility (Figure 1), have a much higher bioavailability with a longer half-life compared to dopamine. Pramipexole has an oral bioavailability of ~90%, a long half-life (between 11•6-14•1 hours), minimal metabolism (70-78% excreted unchanged in urine) and is primarily eliminated via the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…This high spread in the jejunal microbiota composition upon exposure to PD medication implies that the medication has a stronger effect on the jejunal motility. This effect could be due to the rapid absorption of the drugs in the proximal small intestine 70,72,73 , resulting in the highest local drug concentration in the proximal small intestine. Plausibly, these drugs could also elicit a direct effect on the microbiota, which warrants further elucidation.…”

Section: Discussionmentioning

confidence: 99%

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Parkinson' disease medication alters rat small intestinal motility and microbiota composition

Kessel

Bullock

Dijk

et al. 2021

Preprint

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Parkinson's disease (PD) is known to be associated with altered gastrointestinal function and microbiota composition. Altered gastrointestinal function is key in the development of small intestinal bacterial overgrowth, which is a comorbidity often observed in PD patients. Although PD medication could be an important confounder in the reported alterations, its effect per se on the microbiota composition or the gastrointestinal function at the site of drug absorption has not been studied. To this end, healthy (i.e., not PD model) wild-type Groningen rats were employed and treated with dopamine, pramipexole (in combination with levodopa/carbidopa), or ropinirole (in combination with levodopa/carbidopa) for 14 sequential days. Rats treated with dopamine agonists showed a significant reduction in the small intestinal motility and an increase in bacterial overgrowth in the distal small intestine. Importantly, significant alterations in microbial taxa were observed between the treated and vehicle groups, analogous to the changes previously reported in human PD vs HC microbiota studies. These microbial changes included an increase in Lactobacillus and Bifidobacterium, and decrease in Lachnospiraceae and Prevotellaceae. Importantly, certain Lactobacillus species correlated negatively with the plasma levels of levodopa. Overall, the results highlight the significant effect of PD medication per se on the gut microbiota, and the disease-associated comorbidities, including gastrointestinal dysfunction and small intestinal bacterial overgrowth.

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Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs

Murata

Noda

Kohno

et al. 1990

Biopharm & Drug Disp

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Pharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N-(N-acetyl-L-methionyl)0,0-bis-eth-oxycarbonyl) dopamine(1). Plasma concentrations of DA, DA-SO4, and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first-pass metabolism for the formation of DA-SO4 and DOPAC. Though plasma concentration of DA was quite different from that of DA-SO4 or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA-SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N-(N-acetyl-L-methionyl)dopamine(2), DA-SO4, and DOPAC after oral administration of 1 were simultaneously analysed using the compartment model including the first-pass metabolism and two-fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of 2(K4) is larger than that of DA-SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially played an important role to the reduction of first-pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of reduction of first-pass metabolism of DA.

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Bioavailability and Pharmacokinetics of Oral Dopamine in Dogs

Cited by 12 publications

References 4 publications

Parkinson’s Disease Medication Alters Small Intestinal Motility and Microbiota Composition in Healthy Rats

Parkinson’s Disease Medication Alters Small Intestinal Motility and Microbiota Composition in Healthy Rats

Parkinson' disease medication alters rat small intestinal motility and microbiota composition

Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs

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