Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Adequacy of study:

other information

Objective of study:

other: Explanatory disposition study of substance in female rabbits

Qualifier:

according to guideline

Guideline:

other: Internal company method in accordance with company standard operating procedure.

GLP compliance:

yes

Specific details on test material used for the study:

Composition:
99.2% L-654,969, 0.2% lovastatin ammonium salt, 0.2% triol

Radiolabelling:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

female

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

0.5% aqueous methylcellulose

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

Female: 1 animals at 0 mg/kg
Female: 3 animals at 50 mg/kg

Control animals:

yes

Blood and urine samples were taken at intervals for 48 hours after dosing, and analysed for the parent drug and its metabolites by HPLC, and also by enzyme assay of HMG-CoA reductase inhibitory activity.

HPLC results showed maximum plasma levels of the open acid form of MK-733 (the active metabolite- also the notified substance) at 30 minutes after dosing (mean 11.4ug/ml).At 6 hours levels had dropped to 1.1ug/ml and by 24 and 48 hours after dosing were beyond the limits of detection. The 'area under curve (AUC)' O-4 hr was 12850 mg/ml.hr, which is approximately 8 times that found in dogs receiving the same dose (AUC 1673 mg/ml.hr).The active metabolite was not detected in urine during the 48hr period after dosing, indicating extensive metabolism to other products.

Similar studies have been carried out in monkeys, dogs, rats.

Conclusions:

This study, carried out with the prodrug MK-733, shows rapid conversion to the notified substance. In a multiple dose study in 12 female rabbits, dosed with 50mg/kg/day for 10 days, plasma levels 30 minutes after dosing were 24.6 ug/ml on day 1, 37.2ug/ml on day 5 and 30.2 ug/ml on day 10. Faecal excretion of either the prodrug or the active metabolite was less than 10% of total dose, urinary excretion was not measured.

Description of key information

This study, carried out with the prodrug MK-733, shows rapid conversion to the notified substance. In a multiple dose study in 12 female rabbits, dosed with 50mg/kg/day for 10 days, plasma levels 30 minutes after dosing were 24.6 ug/ml on day 1, 37.2ug/ml on day 5 and 30.2 ug/ml on day 10. Faecal excretion of either the prodrug or the active metabolite was less than 10% of total dose, urinary excretion was not measured.

Blood and urine samples were taken at intervals for 48 hours after dosing and analysed for the parent drug and its metabolites by HPLC, and also by enzyme assay of HMG-CoA reductase inhibitory activity.

HPLC results showed maximum plasma levels of the open acid form of MK-733 (the active metabolite- also the notified substance) at 30 minutes after dosing (mean 11.4ug/ml).At 6 hours levels had dropped to 1.1ug/ml and by 24 and 48 hours after dosing were beyond the limits of detection. The 'area under curve (AUC)' O-4 hr was 12850 mg/ml.hr, which is approximately 8 times that found in dogs receiving the same dose (AUC 1673 mg/ml.hr).The active metabolite was not detected in urine during the 48hr period after dosing, indicating extensive metabolism to other products.

Similar studies have been carried out in monkeys, dogs, rats.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential