• Penicillin G and Penicillin V Pharmacology and Therapeutics

  • Pharmacokinetics:  Absorption, Distribution, Metabolism, Excretion (ADME)

    • Absorption

      • The single most important pharmacokinetic difference between the two natural penicillins is their stability in gastric acid.

        • Penicillin G is acid-labile and is largely destroyed in the acidic environment of the stomach, precluding its use as an oral agent.¹

          • Penicillin G must be administered parenterally (intravenously or intramuscularly) to bypass the gastrointestinal tract and achieve therapeutic systemic concentrations.

            • In contrast, the phenoxymethyl side chain of penicillin V confers acid stability, allowing it to survive passage through the stomach and be absorbed in the small intestine.²  

            • For optimal absorption, penicillin V should be taken on an empty stomach (at least 1 hour before or 2 hours after a meal), as food can interfere with its uptake.³

        • Depot Formulations

          • The rapid renal excretion of aqueous penicillin G results in an extremely short elimination half-life of approximately 30 minutes, which would require very frequent dosing to maintain therapeutic levels.

            • This pharmacokinetic limitation was overcome by the development of depot formulations.

              •  By creating less soluble salts of penicillin G with large organic molecules, intramuscular injected drugs act as a reservoir, slowly releasing the active drug over time.³

                • Aqueous Penicillin G (Potassium/Sodium)

                  • This is the high-and-fast option.

                    • Administered intravenously, it provides rapid, high peak concentrations, making it ideal for treating severe, acute infections in a hospital setting where continuous or frequent dosing (e.g., every 4-6 hours) is feasible and high drug levels are necessary.^2,4,5

                • Procaine Penicillin G

                  • This is the medium-and-daily option.

                    • The procaine salt is more slowly absorbed from the IM depot, maintaining therapeutic concentrations for about 12 to 24 hours.

                    • This approach allows for once- or twice-daily dosing, suitable for moderately severe infections that can be managed on an outpatient basis or as step-down therapy from IV treatment.^6,7 

                • Benzathine Penicillin G

                  • The benzathine salt is poorly soluble, resulting in extremely slow hydrolysis and absorption from the IM site.^2,3,

                    • A single injection can provide continuous, albeit very low, therapeutic concentrations for up to four weeks.

                    • This administration profile is suited for eradicating highly sensitive organisms where prolonged, uninterrupted exposure is more critical than high peak concentrations.

                      •  A notable example of this administration method is n the treatment of syphilis (Treponema pallidum).^6,8,9 

                        • Treponema pallidum

                          "Colorized electron micrograph of Treponoma pallidum, the bacteria that cause syphilis. Several spiral -shaped bacteria have been highlighted in gold." November 25, 2022. Attribution NIAID, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons

    • Distribution

      • Once absorbed, both penicillins distribute into body fluids and tissues.

      • Penicillin V is more highly bound to plasma proteins (approximately 80%) compared to penicillin G (approximately 60%).²

        • The highest tissue concentrations for both drugs are found in the kidneys, reflecting their primary route of elimination. ²  

      • Distribution into certain protected sites, such as the central nervous system (CNS), prostate, and eye, is generally poor.

        • Penicillins do not readily cross the blood-brain barrier in healthy individuals.²

          • However, in the presence of inflammation, such as in bacterial meningitis, the permeability of the blood-brain barrier increases, allowing for significantly higher and often therapeutic concentrations of penicillin to enter the cerebrospinal fluid (CSF).

          • Similarly, concentrations in synovial and peritoneal fluids are higher during active inflammation.²

    • Metabolism

      • Penicillin G and V are minimally metabolized.

        • Penicillin G/V are handled as unchanged drugs.  A limited amount of penicillin G undergoes hepatic metabolism to the inactive metabolite, penicilloic acid.^2,4

          •  Penicilloic acid is the major metabolite and is responsible for penicillin’s hapten formation leading to allergic reactions.¹⁰ 

          • Trace amounts of 6-aminopenicillanic acid (the core penicillin structure) and minor metabolites are also recovered in urine.⁴

        • Penicillin V undergoes metabolism in the range of 35%-70% of an oral dose metabolized to penicilloic acid.¹¹

          • Penicillin effects on cytochrome P450 enzymes are typically quite limited and are unlikely to produce clinically relevant drug-drug interactions.¹² 

    • Excretion

      • The kidneys are the principal route of elimination for both penicillin G and V.

        • Penicillins are excreted rapidly in urine via a combination of glomerular filtration and primarily active tubular secretion in the proximal tubules.⁴ 

          • About 60–90% of an IM dose of penicillin G is eliminated in the urine within the first hour due to efficient tubular secretion.

          • The plasma half-life of penicillin G in adults with normal renal function is only about 30–60 minutes^3,4 

          • Penicillin V’s half-life is similarly short (on the order of 30 minutes to 1 hour), necessitating dosing four times daily for oral penicillin V to maintain therapeutic levels.¹³ 

          • Because of this very rapid clearance, frequent dosing or continuous IV infusions are used for serious infections to keep levels above the minimum inhibitory concentration (MIC).¹³ 

      • Probenecid, a uricosuric drug, prolongs penicillin levels by competing for the same organic anion transporter (OAT) in the renal tubule, thereby blocking penicillin’s secretion.¹³ 

        • Co-administering probenecid can increase penicillin AUC and was used in the past to stretch limited penicillin supplies.¹³ 

          • Probenecid is sometimes employed to maintain high penicillin concentrations in severe infections like neurosyphilis or endocarditis.^14,15 

        • A smaller portion of penicillin elimination is non-renal: a fraction is cleared via biliary excretion, and minor metabolism contributes as noted.⁴   In renal impairment, penicillin’s clearance is reduced and dosage or interval should be adjusted to avoid accumulation (which could increase risk of se

      • In summary, the pharmacokinetics of penicillin G and V are characterized by rapid absorption (for acid-stable forms), wide distribution, minimal metabolism, and rapid renal excretion, making them very effective in appropriate clinical settings.

August, 2025