The phthalidyl ester (BRL.8988, talampicillin) of ampicillin gave serum levels in man two and a half times those obtained with ampicillin itself.Ampicillin, D-a-aminobenzylpenicillin (Ia, Fig. 1 To determine the susceptibility of BRL.8988 to hydrolysis, rates were measured over a period of 25 min in aqueous solution and human tissue homogenates as outlined in Table 1. Pivampicillin was included for comparison. It will be observed that, in buffer at pH 7.4, both BRL.8988 and pivampicillin hydrolyzed slowly to ampicillin, the rate for BRL.8988 being slightly faster. At pH 2.0 both compounds were stable to hydrolysis. In human small intestine homogenate both compounds were completely hydrolyzed after 15 min to ampicillin and this was also the case in human whole blood. However, in 2% human blood and in human liver homogenate, BRL.8988 was hydrolyzed at an appreciably faster rate than pivampicillin. Likewise in 90% human serum, BRL.8988 was 80% hydrolyzed to ampicillin after 3 min compared with less than 10% hydrolysis of pivampicillin.A 371-mg amount of BRL.8988 as its hydrochloride, equivalent to 250 mg of ampicillin,
Lactonyl esters of ampicillin and other penicillins have been synthesized as prodrugs designed to improve the oral absorption of the parent penicillins. In general, the esters hydrolyzed rapidly in the presence of tissues including blood and certain of the esters were better absorbed than the parent penicillin. The phthalidyl ester of ampicillin [talampicillin (British Pharmacopoeia approved name), BRL 8988] was selected for extended studies. The compound was found to be well absorbed in various animal species and gave ampicillin serum concentrations in fasting human volunteers 2.5-3 times those obtained for ampicillin itself.
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